6-azido-6-dehydro steroids of the progesterone series,methods for their manufacture and intermediates produced therby

ABSTRACT

6-AZIDO-6-DEHYDROPROGESTERONES AND 6-AZIDO-1,6-BIS-DEHYDROPROGESTERONES POSSESS PROGESTATIONAL AND ANTI-ANDROGENIC PROPERTIES. PREFERRED ARE THE 6-AZIDO-16-METHYLENE17A-LOWER ALKANOYLOXY-4,6-PREGNADIENE-3,20-DIONES. COMPOUNDS USEFUL AS INTERMEDIATES ARE 6B-AZIDO-7A-HYDROXYPROGESTERONES AND THE 7A-ACYLATES THEREOF. THE 6-AZIDO-6-DEHYDROPROGESTERONES ARE PREPARED BY TREATING A 6A, 7A-OXIDO-4-PREGNENE WITH AN ALKALI METAL AZIDE IN AN AQUEOUS INERT ORGANIC SOLVENT; ESTERIFYING THE THEREBY FORMED 6B-AZIDO-7A-HYDROXY-4-PREGNENE; AND TREATING THE RESULTING 6B-AZIDO-7A-ACYLOXY-4-PREGNENE WITH A TETRAALKYLAMMONIUM HALIDE IN AN APROTIC SOLVENT. ALTERNATIVELY, THE 6-AZIDO-4,6-PREGNADIENES ARE PREPARED BY TREATING A 6B-AZIDO-7A-HYDROXYPROGESTERONE OR 7A-ACYLATE THEREOF WITH CONCENTRATED HYDROCHLORIC ACID IN A LOWER ALKANOIC ACID IN AN INERT SOLVENT.

States Patent No Drawing. Continuation-impart of abandoned application Ser.-No. 58,163, July24, 1970. This application July 11, 1972, Ser. No. 272,937

' 1 3 Int. Cl. C07c 173/10 US. Cl. 260239.55 v 26 Claims ABSTRACTOF THE DISCLOSURE 16-azido-6 dehydroprogesterones and 6-azido-1,6-bis-dehydroprogesterones possess progestational and anti-androgenie properties. Preferred a're'the '6-azido-16-methylene 17'a-lower"alkanoyloxy-4,G regnadiene-S,20-diones. Compounds useful as intermediates are 6fl-a'zido7a-hydroxyprogesterones and the 7a-acylates thereof.

The 6-azido-6 dehydroprogesterones are prepared by treating a 6a,7a-oxido-4-pregnene with an alkali metal azide in'an aqueous inert organic solvent; esterifying the thereby formed 6/3azido-7a-hydroxy 4 pregnene; and treating theresulting 6B-azido-7ot-acyloxy-4-pregnene with a tetra'alkylammoninm halide in an aprotic solvent. Alternatively, the 6-azido '4,6-pregnadienes are prepared by treating a 65-azido-7a-hydroxyprogesterone or 7u-acylate thereof withconcentrated hydrochloric acid in a lower alkanoic acid in an inert solvent.

The 6-az ido-1,4,6rpregnatriene 3,ZO-diones are prepared by treating a 6-azido-4,6-pregnadiene with 2,3-dichloro- 5,6-dicyanobenzoquinone in the presence of a strong acid and water.

This is-a continuation of-application Ser. No. 58,163, filed July 24, 1970, now abandoned.

' FIELD OF'THE INVENTION This invention relates to compositions of matter and to processes for their preparation.

More specifically, this invention relates to compositions of matter which may be classified as 6-azido-6-dehydrosteroids of the progesterone series,1to methods for their manufacture, and to intermediates produced thereby.

= SUMMARY OF THE INVENTION alkali metal azide (preferably sodium azide) in an aqueous, non-reactive organic solvent esterifying the thereby formed 6fl-azido-7a-hydroxyprogesterone, and treating the resulting 6B-azido-7aacyloxyprogester0ne with a tetraalkylammonium halide (preferably tetramethylammonium fluoride) in an aprotic solvent whereby is formed a o-azido-6-dehydroprogesterone of our invention.

The invention sought to be patented in another process aspect provides another method for preparing the preferred 6-azido-G-dehydroprogesterones of our invention and resides in the concept of treating a member selected from the group consisting of a 6,8-azido-7a-hydr0xy-progesterone and the 7ot-acyloxy derivatives thereof with concentrated hydrochloric acid in a lower alkanoic acid (preferably acetic acid) in an inert solvent, e.g. acetone or dioxane, whereby is formed a 6-azido-6-dehydroprogesterone of our invention.

The invention sought to be patented in yet another process aspect resides in the concept of a method for preparing 6 azido-l,6-bis-dehydroprogesterones which comprises treating a 6-azido-6-dehydroprogesterone in an inert position-of-matter aspect :resides in the concept of a chemical compound having *a molecular structure comprising a steroid with a progesteronenucleus and having an. azido .group at C ;6 and a hydroxyl group or ester thereof at C 7 which are useful mainly as intermediates in preparing the pharmacologically.active azido-6-dehydroprogesterones of our invention. l.

The invention sought to belpatented in one process aspectfresides'in the concept of "preparing the preferred 6-aZido 6 dehydroprogesterones -of our invention which comprises treating a 6a,7a-oxidoproge'sterone "with an solvent with 2,3-dichloro-5,6-dicyanobenzoquinone in the presence of a strong acid and, frequently, also in the presence of water, whereby is formed a 6-azido-1,6-bis-dehydroprogesterone of our invention.

GENERAL DESCRIPTION OF THE 6-AZIDO-6-DE- HYDROPROGESTERO-NE PRODUCT ASPECT OF THE INVENTION The composition of matter aspect of this invention includes compounds selected from the group consisting of 6-azido-G-dehydroprogesterones of the fOllOWing structural Formula I and the l-dehydro analogs thereof:

Na I

and W taken together with Q when Q is a-hydroxy and. W is (HflXrhYdlOXY), the 16a,17a-alkylidene derivatives thereof;

X is a member selected from the group consisting of hy- 2 drogen and halogen having an atomic weight less than Y is a member selected from the group consistingof hydrogen, oxygen (Hp-OH), and (H43 halogen of atomic weight less than 100) provided X is halogen; and

Z is a member selected from the group consisting of hydrogen and halogen (preferably fluorine).

The alkyl groups included within the definition of the substituents W and T are preferably lower alkyl groups, i.e.'hydrocarbon radicals having preferably up to four carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec.-butyl, and tert.-butyl, although higher homologs such as pentyl and hexyl come within the scope of this invention.

The alkylidene groups contemplated in the compounds of our invention are preferably lower alkylidenes, i.e. hydrocarbon radicals having preferably up to four carbon atoms and having a terminal double bond, including radicals such as methylene, ethylidene, n-propylidene, isopropylidene, n-butylidene, and sec.-butylidene and the like. The 16-lower alkylidene derivatives of this invention (i.e. when W in above Formula I is =CHT) are double bonded to the D-ring at C16. The 1606,1706-fllkY1ld6116- dioxy derivatives have the alkylidene terminal bonds attached to diflerent oxygen atoms, i.e. to the oxygens at C16 and -17 in the case of the 16,17u-alky1idenedioxy derivatives.

As used in the specification and claims of this application, the term acyl denotes an organic radical derived from an organic acid by the removal of the hydroxyl group, e.g. acetyl is the acyl radical of acetic acid, benzenesulfonyl is the acyl radical of benzcnesulfonic acid, and benzoyl is the acyl radical of benzoic acid.

The acyl radicals of the compounds of this invention as defined by Formula I hereinabove include those derived from hydrocarbon carboxylic acids having up to 12 carbon atoms which may be saturated, unsaturated, straight chain or branched chain, aliphatic, cyclic, cyclicaliphatic, aromatic, aryl-aliphatic, or alkyl-aromatic, and may be substituted by hydroxy, alkoxy containing from 1 to 5 carbon atoms or by halogen such as fluorine, chlorine, or bromine. Typical ester groups of the 6-azido-6- dehydroprogesterones of our invention are thus derived from hydrocarbon carboxylic acids such as alkanoic acids exemplified by formic, acetic, propionic, trimethylacetic, butyric, iso-butyric, valeric, iso-valeric, caproic, caprylic, capric, undecylic and lauric acids; substituted alkanoic acids such as phenoxyacetic, trifluoroacetic, and B-chloropropionic acids, aromatic and substituted aromatic acids including benzoic, toluic, p-chlorobenzoic acids; arylalkanoic acids such as phenylacetic and phenylpropionic acids; unsaturated acids such as acrylic and sorbic acids; and dibasic acids such as succinic, tartaric and phthalic acids.

The term lower alkanoyloxy is contemplated as including acid radicals of lower alkanoic acids having preferably up to eight carbon atoms such as radicals obtained from acetic, propionic, butyric, valeric, caprylic, caproic, tert.-butylacetic acid and the like.

The halogens at C9 as defined by X in above Formula I are bromine, chlorine, and preferably fluorine. The halogens at C-21 asdefined by Z in above Formula I are fluorine, chlorine, bromine and iodine, the 21-bromoand 21-i0dopr0gesterones of this invention being valuable mainly as intermediates.

The physical embodiment of the 6-azido-6-dehydroprogesterones of Formula I and the l-dehydro-analogs thereof are characterized by being crystalline solids, usually off white to tan in color, which are insoluble in water and soluble in most organic solvents, particularly in dioxane, although of limited solubility in dialkyl ethers and alkyl hydrocarbons.

The new compounds defined by Formula I possess pharmacological and therapeutic properties and may be used as medicaments in conditions requires a progestational agent, e.g. in fertility control and in the management of various menstrual disorders. They may be administered via the oral or intramuscular route in a manner similar to that in which known progestational agents, e.g. progesterone, are administered, the dosage depending on the age and size of the patient and in the nature and severity of the ailment being treated. The progestational activity of compounds of Formula I was demonstrated in studies in immature rats by the well known Clauberg method via the oral and intramuscular route.

For example, in this test, 6-azido-l6-methylene-l7a acetoxy-4,6-pregnadiene-3,ZO-dione is about 20 times as ac-' tive as progesterone via the intramuscular route.

Our new compounds are also useful in the treatment of disorders requiring anti-androgen therapy such as in the treatment of acne, or benign prostatic hypertrophy. The anti-androgenic activity of compounds of Formula I was studied in the intact male immature rat by the test described by R. O. Neri et al., Eur. J. Pharm. 1, 438-444 (1967 (Section 2.1.2, p. 439). It was demonstrated, for 7 example, that at 10 mgm/kgm. doses administered subcutaneously in sesame o'il, anti-androgenic activity was exhibited by compounds of Formula I, e.g. 6-azido-16- methylene-17u-acetoxy-4,6-pregnadiene-3,ZO-dione.

Typical formulations incorporating the active 6-azido- T being H, lower alkyl, chlorine, fluorine) exemplified by compounds such as:

6-azido-16-methylene-17a-acetoxy-4,6-pregnadiene- 3,20-dione, 1

6-azido-1 6n-butylidene- 17 a-acetoxy-4,-6-pregnadiene- 3,20-dione,

fi-azidol fi-methylene-l7a-propionoxy-4,6-pregnadiene- 3,20-dione, I t

6-azido-9a,1 lp-dichlorol 6-methylene-17a-acetoxy- 4,6-pregnadiene-3,20-dione,

6-azido-9'a,1 lB-dichloro-16-ethylidene-17ot-acetoxy- 4,6-pregnadiene-3,20-dione,

6-azido-9a-bromo-1 l B-fiuorol 6-methylene-17a-acetoxy- 4,6-pregnadiene-3,ZO-dione,

6-azido-9u-fiu0ro-16-methylene-l7a-acetoxy-4,6-

pregnadiene-3 ,l 1,20-trione,

6-azido-1 1 fi-hydroxyl 6-methylene-17a-acetoxy-4,6-

pregnadiene-3,20-dione,

6-azido-l6-methylene-17a-acetoxy-4,6-pregnadiene- 3,1 1,20-trione, v

6-azidol 6-methylene-l7a-acetoxy-2l-fluoro-4,6-

pregnadiene-3,20-dione,

6-azido-9a,1 lfl-dichloro-Zl-fluoro- 1 6-methylen'e-17- acetoxy-4,6-pregnadiene-3,20-dione,

6-azido-16-chloromethylene-4,6-pregnadiene-17w acetoxy-4,6-pregnadiene-3,20-dione,

6-azido9m-fluoro-16-chloromethylene-17a-acetoxy- 4, 6-pregnadiene-l l fi-ol-3,20-dione,

6-azido-l fi-fluoro'methylene-l7a-acetoxy-4,6-pregnadiene- 3,20-dione,

6-azido-9 a-fluoro- 16-fiuoromethylene- 17 a-aceto-xy- 4,6-pregnadiene-1 1 52-01-3 ,20-dione,

6-azido-16-chloromethylene-17u-acetoxy-4,6-pregnadiene-l 1fl-ol-3,20-dione,

and the analogous 17a-hydroxy derivatives of the aforesaid compounds.

Of the foregoing these 6-azido-16-methylene-l'lu-lower alkanoyloxy-6-dehydroprogesterones which are unsubstituted at C9, C-11, and C2l (i.e. compounds of Forac'etoxy-4,6-pregnadiene-3,ZO-dione.

Included among the compounds of our invention are 6-azido :,170: dihydroxy-6-dehydroprogesterones of Formula I and their 16a,l7a-iso-propylidene derivatives (i.e. compounds of Formula I wherein W is (I-LaQI-I) and Q is hydroxy and their 16a,l7u-alkylidene derivatives) exemplifiedby-compounds such as: 6 azido-16a,1'Za-dihydroxy 4,6pregnadiene-3,20-

.dione a'ndlthe l6ot,l7 t-iso-'propylidene derivative thereof, 1 1' 6-azido-9a,1 1 3-dichl0ro-16a,17ot-dihydroXy-4,G-pregnadiene-3,20-di,one and the 16a,'17 t-i so-propylidene derivative thereof, 6-azido-9a-fluoro l 13, 16a, 17mtrihydroxy-4,6-pregnadiene-3,20-dione' and the 16,17a-iso-propylidiene deratives thereof.

Our invention also includes '6-azido-17a-lower alkanoyloxy-6-dehydroprogesterones having a lower alkyl group at 0-16 such as:

6-azido-16/9-methyl-17a-acetoxy-4,6-pregnadiene- 3,20-dione and the 16rx-methyl"ep imer thereof, 6-azido-9u,1 1 ,B-dichlordl 6 3-m'ethyl-17u-acetoxy-4,6-

' pregnadiene-3,20-dione and the .lfia-methyl epimer thereof, 7 6-azido-16,6-niethyl 17u-acetoxy-4,6-pregnadiene- 3,11,20-trione and the 16aemethyl ,epimer thereof, 6-azido-l 6,3-methyl-17a acetoXy-4,6-pregnadiene-1 1/3- ol-3,20-dione and the Ida-methyl epimer thereof, 6-azido-9ot-fiuoro-16 8-rnethyl-l7a-acetoXy-4,6-pregnadiene-3,11,20-trione and the16u-epimer thereof, 6-azido -9a'-fluor'o-1 IB-hydroxy 16B-methyl-1h-acetoxy- ,4,6-pregnadiene-3,ZO-dibne andthe 16u-methyl epimer 6-azid o-9u,1 l d-dichloro-16,8-methyl-17a-acet0xy-4,6-

thereof, and I 6-a'zido-16;3-rnethyl-17a-acetoxy-2-1-fluoro-4,'6-pregnadiene -3,20-dione andthe loot-methyl epimer thereof.

The corresponding 17a-hydroxy analogs of the foregoing are also contemplated as within the scope of our invention, said compounds being useful mainly as intermediates inpreparing the-17-acyloxy compounds of Formula 1.

Other compounds of our invention include 6-azido-16- unsubstituted 170a hydroXy-Z1-fiuoro-6-dehydroprogesterones and 16-lower alkyl analogs thereof which have topical anti-inflammatory activity; Typical compounds of this group include the following:

6-azido-9a,21-difluoro-4,6-pregnadiene-17a-ol-3,11,20-

trione and the 16ix-methyl and lop-methyl analogs thereof; v

6-jazido-9a',21-difiuoro-4,6-pregnadiene-1 1/3, l7oc-diO1-3,20-

dione and the Mot-methyl and l6j3-methyl analogs thereof;

6-azido-21-fiuoro-4,6-pregnadiene 17a-ol-3, 1 1,20-trione and the 16a-methyl and IGfl-methyl analogs thereof;

6-azido-21-fluor0-4,'6pregnadiene-'17ot-ol-3,20-dione and the '16a-methyl and 16,3-methyl analogs thereof.

and 16,8-methyl, homologs thereof;

6-az do-4,6-pregnadiene-1 1p-ol-3,20-dionemethyl and 16B-methylhomologs thereof, 6-azido-9a-fluoro-11fi-hydroxyl,6;pregnadiene-3,20- dione and them -methyl and16fi rnethyl homologs thereof,

and; the 1611-;

6-azido-9u,llfi-dichlorol,6-pregnadiene-3 ,20 dioneand the low-methyl and ,16fi-methyl homologs thereof,"

6-azido-9oc-bromo-1'1B-chloro-4,6-pregnadiene-3,20-di0ne 'and the l6a-methyl and l6fl-methyl hon'iologs thereof, and, v

6-azido-9a, 1 lp-dichloro-21-fluoro-4,6-pregnadiene-3,20-

dione and the 16a-methyl and 16,8-methyl homologs thereof. I

GENERAL DESCRIPTION OF 6-AZIDO 7 OXY- GENATED-PR'OGESTERONE COMPOSITION-OF- MATTER ASPECT OF THE INVENTION wherein V is a member selected from the group consisting of hydrogen and an acyl radical of an acid selected from the group consisting of a hydrocarbon carboxylic acid having up to eight carbon atoms, and a hydrocarbonsulfonic acid having up to 7 carbon atoms;

X is a member selected from the group consisting of hydrogen and a halogen having an atomic weight less than 100;

Y is a member selected from the group consisting of hydrogen, oxygen, (H,;8OH), (H,fi halogen of atomic weight less than 100) provided X is halogen, (H,uOV') provided X is hydrogen, V being a member selected from the group consisting of hydrogen and an acyl radical of a hydrocarbon sulfonic acid having up to 7 carbon atoms, and Y and X taken together are members selected from the group consisting of a 9(11)-dehydro bond and a 95,11,3-ep0xy group;

and wherein Q, W, and Z are as defined hereinabove for Formula I. Typical intermediates of Formula II include compounds such as:

6fl-azido 7oz hydroxy l6 methylene 17oz acetoxyprogesterone (i.e. GB-azido 7a hydroxy 16 methylene 17a acetoxy 4,6 pregnadiene-3,20-dione), the 7 -acetate ester thereof, the 7-methanesulfonate ester thereof and the 7-p-toluenesulfonate ester thereof:

6B-azido 7a hydroxy 16 ethylidene 17a acetoxy- 4,6 pregnadiene 3,20 dione and the acetate ester thereof;

6fl-azido 7a hydroxy 9oc,11 3 dichloro 16a,17a-

isopropylidenedioxy 4,6 pregnadiene 3,20 dione. and the 7ot-acetate ester thereof; t

6/3-azido 70:,17ot bis hydroxy 911,115 dichloro-21- fluoro 4,6 pregnadiene 3,20 dione and the 7aacetate ester thereof; and. v

Git-azido 7u,17ot 'bis hydroxy 21 fiuoro 4,6- pregnadiene 3,11,20 trione and the 7wacetate esterthereof. p

GENERAL DESCRIPTION OF ONE PROCESS AS- PECT'FOR THE-P=REPARATION OF'6-AZIDO-6-" DEHYDOPROGESTERONES The 6-azido dehydroprogesterones, of our inven: tion (e.g. 6-azi do 7 16 methylene- 17cc acetoxy 1 6 dehydropr'ogesteron'e are conveniently prepared from 'oxido-16-methylene 17 acetoxyprogesterone) via re- 7 actions shown diagrammatically hereinbelow in Chart A wherein substituents Q, W, X, Y, and Z in structural Formulae A, B and C are as defined hereinabove for Formula I:

NaN:

TETRAAKYL- -aeyl AMMONIUM HALIDE CHART A According to our process, a 6a,7a oxido-9u-X-11/3- Y-l6-W-l7a-Q-21-Z-4-pregnene 3,20 dione (Formula A) (e.g. 611,711 oxido 16 methylene 17a acetoxy- 4-pregnene 3,20 dione) is treated with an alkali metal azide (e.g. sodium azide) in a non-reactive, organic solvent, preferably a solvent mixture in which water is present (e.g. aqueous methanol, aqueous dioxane, aqueous dimethylformamide, aqueous methanol/dioxane, aqueous tetrahydrofuran, and the like) under mild conditions in neutral or slightly acidic or basic media whereby the epoxy function is split and there is introduced into the molecule a 6fl-azido 7a hydroxy system to form a novel intermediate of our invention, i.e. a ofi-azido 7a hydroxy 4 pregnene of Formula B (e.g. 6/3-3Zid0-7oc-hY- droxy-l 6-methylene-17a-acetoxy-4-pregnene-3,1 l-dione.

The 7u-hydroxy function in the thereby formed 6 8- azido-7a-hydroxy-9a X 11 3 Y-16-W-17a-Q-21-Z-4- pregnene-3,20-dione (Formula B) (e.g. 6p-azido-7a-hydroxy-lG-methylene-17a-acetoxy-4-pregnene-3,11 dione) is then esterified utilizing known esterification procedures (e.g. that utilizing acetic anhydride in pyridine). Treatment of the resukin'g 618-azido-7a-acyloxy-9a-X-1lfi-Y- 16-W-17a-Q-21-Z-4-pregnene-3,20-dione (Formula C), a novel intermediate of our invention (e.g. 6,8-azido-7aacetoxy-1'6-methylene-17a acetoxy 4 pregnene-3,20- dione) with a tetraalkylammonium halide (e.g. tetramethylammonium fluoride) in an aprotic solvent, preferably acetonitn'le or dimethylformamide, .yields a pharmacologically active 6-azido-9a-X-11/3-Y-16-W-17 -Q-21-Z- 4,6-pregnadiene-3,20-dione of our invention (Compound I), e.g. 6-azido-16-methylene 17a acetoxy-4,6-pregnadime-3,1 l-dione.

Our process provides a convenient, novel method of converting, in good yields, a 6u,7e-epoxy-4-pregnene to the novel, pharmacologically active 6-a zido-4,6-pregnadienes of our invention. Heretofore, it has been unknown to deacetoxylate a 6-substituted 7a acyloxy-4-pregnene with a tetraalkylammonium halide to obtain a 6-substituted-4,6-pregnadiene. We have found, however, that when a 6B-azido-7e-acyloxy-4-pregnene-3,20-dione of Formula II (or Formula C hereinabove) is treated with a tetraalkylammonium halide (e.g. tetramethylammonium fluoride) in an aprotic solvent according to a process aspect of our invention, there is formed, in good yield, a 6-azido-4,6-pregnadiene of Formula I.

In carrying out the,,.first step of the aforedescribed' process whereby a 6a,7a-oxido-4-pregnene-3,20-dione of Formula A is converted to a 6 9-azido-7u-hydroxy-4-pregnene-3,20-dione of Formula B, the alkali metal azide reagent of choice is sodium azide, although there may be used other alkali metal azides such as potassium azide, lithium azide; alternatively, there may also be used quaternary ammonium azides such as tetrabutylammonium azide.

The solvents used in the epoxide splitting step may be any non-reactive, organic solvent in which the steroidal starting compound and the azide reagent are soluble.

By non-reactive, organic solvent is meant an organic solvent which will not react with an alkali metal azide or the steroid substrate under the conditions of the reaction so as to cause transformations which will result in the occurrence of competing side reactions. Included among the non-reactive organic solvent contemplated for the epoxide opening are hydroxylated hydrocarbons (e.g. methanol and tertiary butanol), cyclic ethers (e.g. dioxane) and N,N-dialkyl amides (e.g. dimethylformamide).

The epoxide-splitting step is carried out under mild conditions, usually at temperatures ranging from about 0 C. to about 55 C. and preferably at room tempera-.

ture, with the reaction media usually being maintained at about neutrality (e.g. utilizing dimethylformamide and sodium azide) or slightly basic (e.g. utilizing methanol with sodium azide) or slightly acidic (e.g. utilizing dioxane and methanol as solvent together with a small quantity of aqueous lower alkanoic, acid or, alternatively of aqueous boric acid). When carrying out this step on a compound of Formula A having primary or secondary ester groups, e.g. compounds wherein W is .(H,a-acyloxy), in order to minimize hydrolysis of the ester function, the epoxide opening step is advantageously carried out in the presence of acid, preferably an acid having the same acyl function as that in the ester groups in the starting steroid A. Thus, 60:,7a-0Xid0 :,17a diacetoxyprogesterone upon treatment with sodium azide in aqueous methanol/ dioxane to which a few milliliters of acetic acid are added yields a 16a,17a-diacetoxy of Formula B, e.g. 6p-azido-7u-hydroxy-16a,17a-diacetoxyprogesterone. A1- ternatively, when carrying out this step on a compound of Formula A having an alkylidenedioxy function (i.e. 16,17-alkylidene derivatives of compounds wherein Q and W are hydroxy) in order to minimize hydrolysis of the alkylidenedioxy function, theepoxide opening step is I advantageously carried out under essentially neutral or slightly basic conditions. Thus, 6oc,7oc-0Xld0-16u,17oL-i$0- propylidenedioxy-4-pregnene-3,20-dione (compound of Formula A) upon treatment with sodium azide in aqueous methanol/dioxane yields a 16a,17u -alky1idenedioxy t derivative of Formula B, 6fl-azido-7a-hydroxy-l6'a,17ixacid (usually about 100 ml. water and about 1 ml. acetic acid per mole alkali metal azide) and the reaction mixture is allowed to stand at room temperature until all the starting material is transformed as determined by thin layer chromatography (usually about 17 hours). The desired 65- azido-7a-hydroxy thereby formed (B) is then conveniently isolated by pouring the reaction mixture into water, extracting the aqueous mixture with an organic solvent, evaporating the combined organic extracts to a residue comprising a 6B azido-7rx-hydroxy-4-pregnene-3,20dione of Formula B (also a compound of Formula II). Purification is effected utilizing known technique including crystallization and thick layer chromatography.

The esterification step of our process (i.e. B C) is usually carried out in basic media, under relatively mild conditions known to esterify secondary hydroxyl groups. Preferably, the esterification is carried out at room temperature in pyridine utilizing large molar excesses of acylating agents which may be an acid halide of an aryl carboxylic acid (e.g. benzoyl chloride) or of a hydrocarbonsulfonic acid (e.g. p-toluenesulfonyl chloride or methanesulfonyl chloride) or an acid anhydride of a lower alkanoic acid having up to eight carbon atoms. In a preferred procedure for carrying out this step whereby the 7a-hydroxy function is esterified, whenever starting steroid (B), already possesses an ester function, the acylating agent used is preferably one having the same acyl radical as that in the starting steroid (B) (e.g. acetic anhydride when the starting steroid (B) is 6 3-azido-7ot-hydroxy-17a-acetoxy-4- pregnene-3,20dione.

The last step of our process whereby a 6fi-azido-7a-acyloxy-4-pregnene-3,20dione (C) upon treatment with a tetraalkylammonium halide is converted to a 6fl-azido-21- oxygenated-4,6-pregnadiene-3,20-dione (I), is usually carried out in an aprotic solvent at temperatures in the range of from about C. to about 80 (3., preferably between 20 C. to about 60 C.

Although anhydrous conditions are usually employed for this last deacyloxylating step of our process, water may be present in small amounts, and there will be formed the desired 6-azido-4,6-pregnadiene.

Thus, treatment of 6p-azido-7a,l7a-diacetoxy-4-pregnone-3,20-dione in acetonitrile with tetramethylammonium fluoride pentahydrate yields 6-azido-4,-6-pregnadiene-17aacetoxyprogesterone in good yield.

Aprotic solvents suitable for use in our process include dimethylsulfoxide, dimethylacetamide, dioxane, tetrahydrofuran, and preferably acetonitrile or dimethylformamide.

Tetraalkylammonium halides are known in the art. In our process, we have found it most convenient to use tetramethylammonium chloride or, preferably, tetramethylammonium fluoride, since they are commercially available and excellent product yields are obtained thereby. When utilizing the commercially available tetramethylammonium fluoride pentahydrate as reagent, usually the water of hydration is removed therefrom by azeotropic distillation with acetonitrile although the reaction will proceed when the pentahydrate is used as reagent. When preparing the anhydrous form of the tetramethylammonium fluoride reagent, the azeotropic distillation is continued until the reagent is a solid at 50 C., at which point it is most suitable for use as a deacyloxylating reagent to convert a 6 8-azido-7a-acyloxy-4-pregnene-3,20-dione to a 6- azido-4,6-pregnadiene-3,20-dione (I) of our invention.

The tetraalkylammonium halide reagents have limited solubility in the aprotic solvents utilized in this process; therefore, it is preferable to stir the reaction mixture when deacyloxylating at C-7 (6). The reaction will proceed without stirring, however, with the tetraalkylammonium halide dissolving as the reaction proceeds.

Generally, when deacyloxylating a 6 3-azido-7u-acyloxy- 4-pregnene-3,20-dione of Formula C, the 6 8-azido-7a-acyloxy intermediate (C) is added (either in the solid state or in solution) to a solution or suspension of tetraalkylammonium halide (present in quantities'ranging from 1.5 moles to 5 moles per mole of steroid) in an aprotic solvent (of which 1 ml. per 10 mgm. of'reagent is generally used). The reaction is stirred or left standing in temperatures ranging between 0 C. to C. until the deacyloxylation at C-7 (6) is completed as evidenced by thin layer chromatography or by spectroscopic evaluation. (Reaction times usually range from 10 minutes to 48 hours.) The resulting 6-azido-4,6-pregnadiene-3,20-dione of Formula I is isolated utilizing known techniques. Usually, the solvent is partially or totally removed in vacuo, then an organic solvent (e.g. methylene chloride, chloroform, ethyl acetate, and the like) is added, the solution poured into water, the layers separated, the organic layer washed with dilute aqueous base (e.g. sodium bicarbonate), dried and evaporated to a residue comprising the desired 6-azido-9u- X-ll-Y-l6-W-17a-Q-4,6-pregnadiene 3,20 dione of Formula I. Purification of this product is effected by known techniques including chromatography and recrystallization methods.

In our process whereby a 6a,7a-oxido-4-pregnene-3,20- dione is converted via three steps to a 6-aZido-4,6-pregnadiene-3,20-dione, the necessary 6u,7a-oxido-4-pregnene- 3,20-dione starting compounds (A) are conveniently prepared according to known procedures from the corresponding 6,7-unsubsituted-4,6-pregnadiene-3,20-dione such as by reaction with a peracid in a non-reactive organic solvent, e.g. with reagent-solvent combinations such as meta-chloroperbenzoic acid in acetone, meta-chloroperbenzoic acid in methylene chloride/tert.-butanol, or with mono-perphthalic acid in chloroformln turn, the 6,7-unsubstituted-4,6-pregnadiene-3,20-dione precursors are conveniently derived from the corresponding 6,7-dihydro analogs by procedures known to effect dehydrogenation between C-6 and C-7, such as those utilizing chloranil or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). When the starting steroid has a 16-a1kyl substituent, e.g. 16/8-methyl- 4-pregnene-3,20-dione, in order to minimize the possibility of rearrangement reactions, introduction of the 6-dehydro bond is preferentially effected by the use of 2,3-dichloro- 5,6-dicyanobenzoquinone in the presence of acid (e.g. DDQ in ethyl acetate and acetic acid).

When preparing the 6-azido-4,6-bis-dehydropregnanes of our invention (i.e. the G-dehydro analogs of Formula I) by the above described process, it is usually preferable to have present in the starting 6a,7a-epoxypregnane (A) all the substituents desired in the final 6-azido-4,6-pregnadiene product, I. Thus, the preferred embodiment of the composition-of-matter aspect of our invention, i.e. the 6-azido-l6-lower alkylidene-l7a-lower alkanoyloxy-6-dehydroprogesterones, may be prepared by this process aspect of our invention, utilizing as starting compounds 6a,7a-epoxy intermediates of Formula A in which the 16- lower alkylidene-17u-lower alkanoyloxy substituents are present which are derived from the corresponding 65- chloro-7rx-acyloxy-16-lower alkylidene-progesterone derivative (e.g. 6 3-chloro-7a,17a-diacetoxy-16-methyleneprogesterone) by reaction With alkaline aqueous alkanol (e.g. aqueous methanolic sodium hydroxide). In turn, the 6 8-chloro-7u-acyloxy-16-lower alkylideneprogesterone precursors are prepared utilizing procedures known in the art. Specifically, a 16-lower alkyl-4,6,16-pregnatriene-3,20- dione (e.g. 16 methyl 4,6,16 pregnatriene 3,20-dione) when treated with at least two moles of an aromatic peracid (preferably meta-chloroperbenzoic acid) in a nonreactive organic solvent (e.g. benzene, methylene chloride or tertiary butanol) will yield a 6a,70c;160t,17ot-biS-OXidO derivative (e.g. 6a,7a;16oz,17ot-biS-OXid0 16B methyl-4- pregnene-3,20-dione) which upon treatment with at least two moles of hydrogen chloride in a lower alkanoic acid (e.g. acetic acid) results in fission of both epoxide functrons to yield a 6fi-chloro-7a,l7a-dihydroxy-l6-lower alkylideneprogesterone derivative (e.g. 6fl-Ch1OIO-7'Ot,17d-di hydroxy-l6-methyleneprogesterone) which, upon esterification via known techniques for esterifying tertiary alco- 11 hols yields the 6fl-chloro-7a,17a-diacyloxy-16-lower alkylideneprogesterone precursor (e.g. 6,B-chloro-7a,17a-diacetoxy-16-methyleneprogesterone for the requisite 60,7ucoxido starting compound of our process as set forth in Chart A.

In the aforementioned esterification step in the preparation of the 6 3-chloro-7u-alkanoyloxy-precursor of the 6a,7 x-oxido starting compound of this process, the choice of acylating agent used will depend upon the ester desired at C-l7 of the 6-azido-16-lower alkylidene-6-dehydro compound of ourinvention. Thus, when preparing 6-azido-l6-methylene-l7a-valeroxy 6 dehydroprogesterone according to the process described hereinabove, the necessary 6u,7a-epoxy-starting compound (e.g. 6oc,70zxido-16-methy1ene 17cc valeroxyprogesterone) is prepared by reacting 16-methyl 4,6,16 pregnatriene-3,20- dione with m-chloroperbenzoic acid in tertiary butanol followed by treatment of the resulting 6a,7a;16a,l7oc-bisoxido-l6-methyl 4 pregnane 3,20 dione with hydrogen chloride in acetic acid, thence esterification of the 65 chloro 7a,].7oz dihydroxy 16 methyleneprogesterone thereby formed with valeric acid in the presence of p-toluenesulfonic acid and trifiuoroacetic anhydride to obtain 6fi-ChlOIO-7oc,17a-diVal6IOXY 16 methyleneprogesterone which, upon treatment with sodium hydroxide in aqueous methanol, will prepare the necessary 6a,7aepoxy starting compound, i.e. 6a,7u-oxido-16-methylene 17a-va1eroxyprogesterone.

Alternatively the 6-azido-16-lower alkylidene-l7a-lo-wer alkanoyloxy 6 dehydroprogesterones of our invention (e.g. 6 azido-l6-ethylidene-17u-propionoxy-4,6-pregnadiene-3,20-dione) are also prepared via our process as shown in Chart A, but utilizing as starting compound a 6u,7a;1 60c,170L-biS-OXldO-16fi-1OWC1 alkyl-4-pregnene-3,20- dione (e.g. 6a,7a;16a,l7a-bisoxido-16fi-ethyl-4-pregnene- 3,20-dione) which are prepared as described hereinabove. In this species of our process, the 6a,7oc;16u,17a-biS-OXld0- 16fi-lower alkyl-4-pregnene-3,20-dione starting compound is a compound of Formula A, Chart A, wherein W and Q together form the l6fi-lower alkyl-l6a,17aoxido functions (shown hereinbelow in Chart '13 as Compound A) which is converted to a 6-aZido-16-lower alkylidene-17mlower alkanoyloxy-fi-dehydroprogesterone as shown in Chart B below via flow diagram wherein substituents X, Y, and Z are as defined hereinabove for Formula I; T being H and lower alkyl:

CH: Z (:0

""0 Y= lower alkyl acylating 0 --0H medium Na B tetraalkyl ammonium halide CHART B By this species of our process, a 9aX-l1B-Y-6a,7a; l6a,l7a-bis-oxido 16B lower alkyl 4 pregnene-3,20- dione (Formula A) (e.g. 6a,7a;16a,17u-bis-oxido-l6flethyl-4-pregneue-3,20-dione) is treated with an alkali metal azide (e.g. sodium azide) in an aqueous organic solvent (e.g. aqueous methanol, aqueous dioxane, aqueous dimethylformamide, aqueous methanol/dioxane and the like) at room temperature to obtain a 9u-X-l1-Y-6/3- aZido-7a-hydroxy-16,8-lower alkyl 16cc, l7a-oXido-4-preg- -nene-3,20-dione (Formula B) (e.g. 6/8-azido-7u-hydroxy- 16/3-ethyl-16a,l7a-oxido-4-pregnene-3,ZO-dione), When a compound of Formula B is subjected to esterification conditions known to esterify tertiary alcohols, e.g. is treated with an acid-acid anhydride mixture of the group consisting of a lower alkanoic acid and the corresponding acid anhydride (e.g. propionic acid and propionic anhydride), an anhydride of a lower alkanoic acid with a strong organic acid (e.g. propionic acid anhydride and p-toluenesulfonic acid), or a lower alkanoic acid with an anhydride of a strong organic acid wherein the pKa of said strong acid is at most equal to the pKa of said lower alkanoic acid (e.g. propionic acid and trifluoroacetic anhydride) the 7a-hydroxy group at C-7 in intermediate B is esterified and the 16u,17a-oxido is split with formation of the alkylidene-17a-alkanoyloxy groups and there is obtained 9oc-X-11-Y-6fi-8ZldO-7oc,17oc-biS-1OW6I alkanoyloxy-l6-methyleneprogesterone derivative (Formula Q) (e.g. 6B azido-7a,17a-dipropionoxy-l6-ethylideneprogesterone) together with some isomeric 15-dehydr0-l6-lower alkyl-l7a-lower alkanoyloxy derivative (e.g. 6,8-azido- 7a,17a dipropionoxy-16-ethyl-1S-dehydroprogesterone). Reaction of a 6B-azid0-7u-acyloxy derivative of Formula C With a tetraalkylammonium halide (e.g. tetramethylammonium fluoride) according to our process in an aprotic solvent (preferably acetonitrile or dimethylformamide) yields a 9u-X-11-Y-6-azido-16-lower alkylidenel7u-lower alkanoyloxy-6-dehydroprogesterone of Formula I (e.g. 6-azido-16-ethylidene-17a-propionoxy-4,6-pregnadiene-3,2'0-dione) The process step B'- C' whereby a 7a-hydroxy function is esterified and a 16B-alkyl-16a,17m-oxido function is converted to a 16-alkylidene-17a-acyloxy derivative, is generally carried out under anhydrous conditions and in an inert atmosphere such as argon or nitrogen. Although any inert solvent such as benzene, toluene, xylene and the like may be used, the preferred solvent is the lower alkanoic acid corresponding to the desired ester at C-17. Thus, acetic acid is preferred when a 17-acetate is de- 13 14 sired and caproic acid is preferred when a 17-caproate is diene-3,20-dione) which, when subjected to esterification to be prepared. conditions known to esterify tertiary alcohols, e.g. by v In both species shown hereinabove in Charts A and B, treatment with a mixture of acetic acid, p-toluenesulfonic there are three steps, the first of which involves the conacid and trifiuoroacetic anhydride, yields a 6-azido-16- version of a 6u,7a-epoxyprogesterone derivative (i.e. dealkylidene-lh-acyloxy compound of Formula I (e.g. 6- rivatives A and A) to a GB-azido-7a-hydroxyprogesterone azido-16-methylene-17a-acetoxy 4,6 pregnadiene-3,20- derivative (derivatives B and B), followed by an esterifidione). Alternatively, treatment of intermediate D with cation step to obtain a 6fi-azido-7a-acyloxyprogesterone hydrobromic acid in acetic acid according to known (i.e. derivatives Cand C) and thence the final deacylmethods will yield a 16-alkylidene-17a-hydroxy comoxylation step at C-7 (6) to obtain a 6-azido-6-dehydro- 10 pound of Formula I (e.g. 6-azido-16-methylene-17a-hyprogesterone (I) of our invention. droxy-4,6-pregnadiene-3,ZO-dione).

The method of Chart B is convenient when preparing a When intermediate B is first treated with hydrobromic 16-alkylidenes progesterone of Formula I wherein O is acid in acetic acid at room temperature, the 16/3-alkyllower alkanoyloxy since the 6ot,7oc;16oz,17u-biS-0Xid0 16u,l7a-oxido function is converted to 16-alkylidene-17- starting compound (A') for this method is prepared in hydroxy groups to form a GB-azido-h-sulfonyloxy interone step from a 6,16-bis-dehydro precursor, whereas four mediate C (e.g. 6p-azido-7a-methanesulfonyloxy-16-methsteps are required to prepare the 6a,7a-oxido-16-lower ylene-17a-hydroxy-4,6-pregnadiene-3,20 di0 e)- T talkylidene-17a-lower alkanoyloxy starting compounds ment of the foregoing with tetramethylammonium halide (A) from the same precursor for the method of Chart A. yields a 16-alkylidene-17a-hydroxy compound of Formula Alternatively, another method for preparing both the I (e.g. 6-azido-16-methylene-17u-hydroxy-4-pregnene-3, 17a-hydroxy and 17a-alkanoyloxy-16-lower alkyidene-4,6- 20-dione). p'regnadlenes of our invention utilizes intermediate B as When preparing 6-azido-6-dehydro progesterones from starting, compound as shown below in Chart C wherein a 6a,7a-0Xido progesterone according to our process as R is a hydrocarbon and wherein T, X, Y, and Z are set forth in Charts A and B, substituents such as those as defined hereinabove for Formula I. at C-9 and at C-ll may be introduced into the molecule Alternatively, another method for preparing both the during the process, preferably after the formation of the 17a-hydroxy and 17a-alkan0yloxy-16-lower alkylidene- 6p-azido-7u-acyloxy-pregnane intermediate (C and C).

4,6-pregnadienes of our invention utilizes intermediate Thus, a 9(11)-dehydro intermediate is prepared utilizing B as starting compound as shown below in Chart C known procedures preferably before formation of the 6- Wherein R is a hydrocarbon and wherein X, Y, and Z azido-6-dehydro-system and after the epoxidation at 0-6 are as defined hereinabove for Formula I; T being hyand 7, and usually after preparation of the 6 3-azido-7w drogen and lower alkyl: acetoxypregnane intermediate (C and C). Thus, an 11- CHzZ CHgZ CHQZ :0 (I) p Bus mam? t tetraalkyl- HOAe/ptSA/TEAA W 0= as? N 'a a CI! D I CHZZ CHzZ --OH CH'I" Y\ -CHT tetraalkyl- Y ammonium halide o:

I CHART C I By this species of our process, a 6fi-azido-7m-hydroxyhydroxyl group is mtroduced microbiologically with the l6fl-lower alkyl-4-pregnene of Formula B (e.g. 6,3-azidoaid of microorganisms such as Curvularia lrmala 7a-hydroxy-,165-rnethyl-16a,17a oxido-4-pregnene-3,20-- (N.R.R.L. 2380) or Rhizopus nigricans (A.T.C.C. dione) is treated with a hydrocarbonsulfonyl chloride in 6227b). When Curvularia lunata is employed, the IIB-hypyridine at room temperature to obtain the corresponding d roxy steroid produced is dehydrated by a reagent such 7a-sulfonyloxy ester intermediate C" (e.g. 6B-azido-7w as methanesulfonyl chloride in the presence of pyridine methanesulfonyloxy 16B,- methyl 16a,17u oxido 4- or phosphorous oxychloride in pyridine or N-bromopregnene-3,20-dione) which, upon treatment with tetraacetamide and sulfur dioxide in pyridine to give the 9 methylammonium fluoride yields the corresponding 6- (11)-dehydro intermediates. Alternatively, the action of a'zid o-16p-lower alkyl-16u,17ot-oxido-6-dehydrointermedi- Rhizopus nigrz'carzs on progesterone yields the Ila-hyate D (e.g. 6-azido-16fl-methyl-16a,17a-oxido-4,6-pregnadroXy derivatives, lla-hydroxy progesterone, i.e. -4-pre2- nane-11u-ol-3,20-dione. Subsequent-treatment with a sulfonyl chloride such as methanesulfonyl chloride yields the corresponding lla-sulfonate, i.e. lla-methanesulfonyloxy- 4-pregnene-3,20-dione. To minimize the possiblity of competing side reactions, the first two steps in our process (as shown in Charts A and B) for introduction of the 6- azido-6-dehydro-system are carried out with the Ila-SUI- fonyloxy-derivative. Thus, treatment of lla-methanesulfonyloxy-4-pregnene-3,ZO-dione with chloranil followed by epoxidation of the 6-dehydro analog thereby formed, i.e. 11oz methanesulfonyloxy-4,6-pregnadiene-3,20-dione with monoperphthalic acid, for example, yields 6u,7uoxido 11oz methanesu1fonyloxy-4-pregnene-3,20-dione which, upon treatment with sodium azide yields fifi-azido- 7a hydroxy 11a-methanesu1fonyloxy-4-pregnene-3,20- dinoe. Esterification at C-7 utilizing acetic anhydride in pyridine yields 6B-azido-7a-acetoxy-1la-methanesulfonyloxy 4-pregnene-3,20-dione. Introduction of the 9(11)- bond is conveniently carried out in the foregoing 11o:- methanesulfonate by treatment with sodium acetate in acetic acid to yield 6/3azido-7a-acetoxy-4,9(11)-pregnadiene-3,20-dione.

After formation of the 9(1l)-dehydro intermediate, halogen groups may then be introduced at C-9 and C11 of the 6p azido 7a-acetoxy-4,9(l1)-pregnadiene-3,20- dione, e.g. to form a 9a,11,8-dichloro derivative employing procedures well-known in the art. For example, treatment of the aforenamed 9(11)-dehydropregnanes with chlorine in halogenated solvents such as methylene chloride will yield the 911,11 fl-dichloro intermediates, 6fi-azido- 7a acetoxy-9a,11B-dichloro-4-pregnene-3,20-dione which upon treatment with tetramethylammonium fluoride will yield 6-azido-9a,11,6-dichloro-4,6-pregnadiene-3,20-dione, a 6-dehydro compound of Formula I. If a 9a-bromo-11fifluoroor a 9a-ch1oro-11fi-fiuoro-derivative is desired, the 6p azido-7a-acyloxy-9(11)-dehydro precursor is treated with N-bromosuccinimide and hydrogen fluoride or N- chlorosuccinimide and hydrogen fluoride, respectively, to obtain the corresponding 9u,11}3-dihalogeno derivative, i.e. 6p azido-7a-acetoxy-9a-bromo-11/8-flu0ro-4-pregnene-3, di0ue and 6 3-azido-7a-acetoxy-9a-ch1oro-1118-fluoro-4- pregnene 3,20-dione, respectively. Treatment of each of the foregoing 6p azido-7a-acetoxy intermediates with tetramethylammonium fluoride according to the above described process yields 6 azido-6-dehydro-9u,1lfl-dihalogeno derivatives of Formula I, e.g. 6-azido-9u-bromo-11flfluoro-4,6-pregnadiene-3,20-dione and 6-azido-9a-ch1oro- 11B-fluoro-4,6-pregnadiene-3,20-dione respectively.

The 66 azido-7a-acetoxy-9(1l)-dehydropregnanes are also useful in the preparation of the 9a-halogeno-l1;8-hydroxy derivatives of our invention. Thus, a 6B-azido-7aacetoxy-pregnane, e.g. 6,9 azido-7a-acetoxy-49(11)-pregnadiene-3,20-dione upon treatment with N-bromoacetamide in aqueous dioxane in the presence of perchloric acid according to known procedures yields the corresponding 9a bromo 11B hydroxy derivative, e.g. 6 3-aZidO-7OL- acetoxy-9a-bromo-1 1p-hydroxy-4-pregnene-3,20-dione.

Other 90: halogeno-l1B-hydroxy-6 8-azido-7u-acetoxy- ZI-oXygenated-pregnane intermediates, i.e. the 9a-chloroand 9a-fluoro-, are obtained from the corresponding 9/3, 113 oxido derivatives, e.g. 6fi-azido-7a-acetoxy-9p,11poxido 4-pregnene-3,20-dione which, in turn, are derived from the aforedescribed 9a-bromo-11/8-hydroxy intermediates, e.g. 6 3-azido-7ot-acetoxy-9a-bromo-11B-hydroxy-4- pregnene-3,20-dione, by treatment with potassium acetate in ethanol or acetone. Addition of hydrogen chloride in chloroform, or of hydrogen fluoride in chloroformtetrahydrofuran, to a 93,11/3-oxido pregnane intermediate, e.g. 6,8 azido-7a-acetoxy-9fl,11,8-oxido-4-pregnene-3,20-dione, will yield the corresponding 9a-chloro-11B-hydroxyor 9afluoro llfi-hydroxy-pregnane intermediates, respectively, e.g. 6/3 azido-7u-acetoxy-9a-chloro-4-pregnene-1113-01-3, ZO-dione and 6/3 azido-7a-acetoxy-9a-fluoro-4-pregnene- 11fi-o1-3,20-dione.

By utilizing the above procedures it is obvious that one need but choose the appropriate 65 azido-7a-acetoxy-9 (1l)-dehydro-intermediate to obtain other 9a-halogenohydroxy-6,8-azido-h-acetoxy-pregnane intermediates of our invention. The 6fi-azido-7a-acyloxy-9a,llfi-dihalogeno-pregnanes and the 6 3-azido-7u-acyloxy-9ot-halogeno- 11B hydroxy-pregnane intermediates prepared from the corresponding 65 azido-7a-acyloxy-9(11)-dehydropregnanes as described hereinabove are then converted to the corresponding 6-azido-4,6-pregnadienes of our invention by treatment with a tetraalkylammonium halide in acetonitrile. Thus, each of 6B azide-7u-acetoxy-9a-bromo-4- pregnene 11/3-ol-3,20-dione, 6/3-azido-7a-acetoxy-9a-chloro-4-pregnene-11B-ol-3,20-dione and 6/3-azido-7a-acetoxy- 9a-fluoro-4,6-pregnadiene-11 3-ol-3,20-dione and the 16 (a and t n-methyl honologs thereof upon treatment with tetramethylammonium fluoride in acetonitrile yields the corresponding 6-azido-9a-halogeno-11/3-hydroxy-4,6-pregnadiene of our invention, e.g. 6-azido-9u-bromo-4,6-pregnadiene 11 3-ol-3,20-dione, 6-azido-9a-chloro-4,6-pregnadiene-11,B-ol-3,20-dione, and 6-azido-9a-fluoro-4,6-pregnadiene-11,8-ol-3,20-dione, respectively, and the 16 (cc and fl)-methyl homologs thereof.

When the starting 6B-azido-7a-acetoxy-4-pregnane has a 9a-bromo-11,B hydroxy group, treatment with tetramethylammonium halide according to our process will cause the formation of a mixture of products including some 9 3,115 oxido-4,6-pregnadiene. Separation of the product mixture may be effected via chromatographic procedures. Thus, treatment of 6fl-azido-7a-acetoxy-9ubromo-11p hydroxy-4-pregnene-3,20-dione with tetramethylammonium fluoride in acetonitrile yields a mixture of 6-azido-9'ot-bromo-11 3 hydroxy-4,6-pregnadiene-3,20- dione together with some 6-azido-9/8-11fi-oxido-4,6-pregnadiene-17u,21-diol-3,20-dione which, when separated on a thick layer preparative plate with silica gel yields mainly 6 azido-9a-bromo-1lfl-hydroxy-4,6-pregnadiene-3,20- dione.

The 9u-halogeno-1l-keto-pregnanes of Formula I may be obtained from the 9'a-halogeno-1lfl-hydroxypregnanes by oxidation of the ll-hydroxy function such as with chromic acid. Alternatively, the 6-azido-9a-halogeno-11- keto-4,6-pregnadienes may be obtained from the 611,70:- oxido-4-pregnene-precursor according to the process described hereinabove. Thus, 6-azido-9a-fluoro-4,6-pregnadiene-3,1l,20-trione is formed upon oxidation of 6-azido- 9u-fluoro-4,6-pregnadiene-11fi-ol-3,20-dione with chromic acid. Alternatively, this 9oz-fluoro-ll ketopregnane is derived from 6a,7a-oxido-9ot-fluoro-4-pregnene-3,11,20-trione which upon treatment with sodium azide in dilute acetic acid is converted to the corresponding 6B-azido-7ahydroxy intermediate, i.e. 6,8-azido-7a-hydroxy-9a-fluoro- 4-pregnene-3,11,20 trione, which after esterification at C-7, such as with acetic anhydride in pyridine, followed by treatment of the thereby formed 7ot-acetate ester with tetramethylammonium fluoride yields the 6-azido-9ot-fluoro-l1-keto'4,6-pregnadiene of Formula I, i.e. 6-azido-9a fluoro-4,6pregnadiene-3, 1 1,20-trione.

GENERAL DESCRIPTION OF ANOTHER PROCESS ASPECT FOR PREPARATION OF 6-AZIDO-4,6- PREGNADIENES Preferred compounds of this invention, i.e. the 6-azido- 4,6-pregnadiene-3,20-diones of Formula I are also prepared from the 6,8-azido-7ot-acyloxy-4-pregnene intermediate of the first process aspect (formulae B and C, chart A hereinabove) by reaction of said 6,B-azido-7 t-hydroxy-v 4-pregnene of Formula B (Chart A) or the 7a-ester thereof (Formula C, Chart A) with concentrated hydrochloric acid in acetone or preferably, in a solvent mixture comprising a lower alkanoic acid (e.g. acetic acid) and dioxane.

In carrying out the physical embodiment of this process aspect, we have found that concentrated hydrochloric acid is necessary in order to dehydrate at C-6 and C-7.

i.e. to convert the '678-azido-7a-hydroxy pregnane or 6,8- azido-7a aeyloxy pregnane to a 6-azido-6-dehydro'pregnane. When other acids are employed such as p-toluenesulfonic acid or sulfuric-acid, "dehydration does not occurandthe 'dp-azido-7a-hydroxy (B, Chart A) or 6B- azido-ja a'cyloxy starting compound (C, Chart A) is recovered ,even after several; days reaction time.

According to our process, a 6p-azido-7a-hydroxy-9u- X-llB-Y-l6-W-17a-Q-21 Z-4 pregnene-3,20 dione (Formula B, Chart A) or aja-acyloxy thereof (Formula C, Chart A)"i's dissolved in either "acetone or preferably a solvent mixture comprising'a lower alkanoic acid (usually acetic acid) and dioxane to which concentrated bydrocliloric acid is added. The reaction mixture is allowed to remain, at room temperature until a thin layer chromatographic analysis of an aliquot of the reaction mixture,'indicatesthe absence 'of a 6flazido-7a-hydroxy or a 6 /3-a zido-7a-acyloxy intermediate. 'The reaction time is usually from 24'to 48 hours, although it may take several days to 'eifect'c'ompleted dehydration in some cases. Thei'resulting 6-azido-4,6-pregnadiene-3,20-dione of Formula I is isolated from the reaction mixture using standard techniques usually'by diluting the reaction mixture with a halogenated solvent (e.g'.-methylene chloride), washing -.the resulting organic solution with water and aqueoussodium bicarbonate solution, distilling the dried organic solution. and purifying the residue via chromatographic techniques. 1 r

The 6B-azido-7a-hydroxy 4 pregnene-3,20-diones of I Formula B,xand the .619'azido-7oeacyloxy-4-pregnene-3,20- 30 dionesof Formula: C, iChart- A,.necessary intermediates inthisfprocess-aspect, are prepared'in the same manner as describedl'hereinabove in the'section relating to the firstprocess aspect. 2 In carrying out the physical embodiment of this process-aspect whereby a 6a,7u-oxido-4-pregnene-3,20-dione of FormulaiA is treated with an alkali metal azide in a non-reactive organic solvent and-the thereby formed 6,8- azido-7a-hydroxy-4-pregnene precursor (Formula A) desirably should possess the'substituents (such as at C-9, l l,"i1 6 and 1-7), which are desirediin the 6@az.ido-4,6-pregnadiene product of Formula I produced thereby. When structural modifications of the pregnane molecule (such asat C 9 or ll) are contemplated, it is usually preferable toutilize as starting compound a 6fl-azido-7a-acyloxy-4-pregnene of Formula II (or Formula C) hereinabove and, after carrying out any desired structural modifications on the 7u-acyloxy intermediate, converting the thereby modified steroid (e.g. a 6 3-azido-7a-acyloxy-9a- X-"ll Y-F6-W l7a-Q-21-Z-4 -pregnene-3,20-dione of Formula IIto the therapeutically active 6-azido-4,6-pregnadiene of Formula I by-"treatrnent' thereof with concentrated hydrochloric acid'or, preferably, with a tetraalkyl ammonium-halide according'to the first process aspect of our invention. T GENERAL DE SCRI FTION F PROCESS FOR PRE- .PARING -AZIDQ 1',,4 ,e*- FREGNATRIENE-BJO- DIONES l The 6-azido-1,4,6-pregnatriene-3,20-diones'of Formula I are prepared,ifrom;thecorresponding '6-azido-4,6-pregad en -iwdionesot Fo mul 1 .:-by the p s aspect of; our inyention wherebysaid -6-azido-4,6-pregnadiene in aninert solvent (preferably dioxane) is reacted with 2,3- dichloro 5, 6-glicyanobenzoquinone :(hereinafter referred to asy'DDQ) in the presence ofa strong acid (preferably hydrochloric acid) and usually also in'the presence of water. According to our. process; ia 6 azido;4,6-pregnadiene- 3,20-dione of Formula I (e.g. 6-azido-16-methylene-17aacetoxy-4,6 pregnadiene 3',ZO-dione 'is treated with an excess (based upo'n m lar ratios) of DDQ in a nOn-reactive, organic solvent (usually benzene or preferablyj dioxane) in the presence of a strong acid (e.g. 'trifluoro-i acetic, sulfuric or,"preferably, hydrochloric acid) advantageously in amounts at least equimolar to' the 6-azido- 10 toxy-4,6-pregnadiene-3,20-dione at 60 C. to the corresponding 6-azido-1,4,6-pregnatriene. When trifluoroacetic acid is employed as the strong acid, the yields and purity of product obtained are similar whether derived from a reaction mixture containing only a trace of water in dioxane or a reaction mixture containing 10% Water in dioxane; however, the reaction rate appears faster with only a trace of water present.

Our reaction is preferably carried out at temperatures in the range of from 60 C. to 80 C. At lower temperatures, the rate of reaction is slower; at higher tempera-' tures, side reactions occur resulting in lower yields of 6-azido-1,4,6-pregnatriene.

Our reaction whereby a 6-azido-4,6-pregnadiene upon treatment with DDQ and a strong acid is converted to a 6-azido-1,4,6-pregnatriene is preferably carried out utilizing concentrated hydrochloric acid as the strong acid. We have found that optimum yields of 6-azido-1,4,6- pregnatriene-3,20-dione with minimum side reactions are obtained from a 6-azido-4,6-pregnadiene-3,20-dione when there is employed from about one to five moles of concentrated hydrochloric acid per mole of steroid and said reaction is carried out at about 60 C. to- 80 C. with the aqueous organic solvent being dioxane containing from about 5% to about 10% water and with the concentration of hydrochloric acid and of the steroid in the aqueous dioxane preferably being from about 1% to about 5% by volume.

We have found that when greater or smaller quantities of acid and/or water are used than those falling within 40 the preferred range, the yield of 6-azido-1,4,6-pregnatriene diminishes with a concomitant increase of side product formation. Additionally, when the concentration of hydrochloric acid or of 6-azido-4,6-pregnadiene in the aqueous dioxane reaction mixture falls outside the 1% to 5% by volume range, or when high temperatures, e.g. over 100 C., are employed, lower yields of 6-azido-l,4,6-pregnatriene with lesser purity are obtained.

We have found a convenient water-solvent-acid for use in our process to be one containing about 9.0% water in dioxane and about 0.4% hydrochloric acid (i.e. a solution containing 49.5 ml. dioxane, 0.5 ml. concentrated hydrochloric acid and 5 ml. water). Optimum yields of 6-azido-1,4,6-pregnatriene are obtained by our DDQ dehydrogenation process when a sufiicient quantity of the aforementioned aqueous dioxane-hydrochloric acid is added to a 6-azido-4,6-pregnadiene so there is present in the reaction mixture from one to five moles concentrated hydrochloric acid per mole of steroid.

In carrying out the physical embodiment of a preferred method of this process, the reaction mixture comprising a 6-azido-4,6-pregnadiene and hydrochloric acid in aqueous dioxane is usually heated under an inert gas, e.g. nitrogen, at temperatures in the range of from about 60 -C..

0 techniques such as pouring the reaction mixture into Water, extracting with an organic solvent and separating the products utilizing chromatographic techniques.

Our process is advanageously (although not necessarily) carried out in the absence of oxygen. Aqueous hy.-'

drochloric acid is preferred as strong acid catalyst a1 though other strong acids such as sulfuric and trifluoro acetic may also be used, usually in the presence of water.

The 6-azido-1,4,6-pregnatrienes of this invention are not easily formed by the usual methods known in the art. Thus, for example, isolatable quantities of 6-azido- 1,4,6-pregnatriene are not obtained when the corresponding 6-azido-4,6-pregnadienes are treated in anhydrous dioxane with DDQ alone or with DDQ in the presence of a weak acid such as benzoic acid, or when subjected to the action of microbiological dehydrogenating agents such as Corynebacterium simplex and Bacillus sphaericus utilizing conventional techniques. Similarly, treatment of a 6fi-azido-7ot-acyloxy-1,4 pregnadriene with a tetraalkylammonium halide according to the first process aspect described hereinabove does not yield isolatable quantities of a -6-azido-1,4,6-pregnatriene of Formula I. It is thus unexpected and particularly advantageous that treatment of a 6-azido-4,6-pregnadiene of Formula I wih DDQ in the presence of a strong acid will yield a 6-azidio 1,4,6-pregnatriene of our invention.

PREPARATION OF ESTERS OF OUR INVENTION 6-azido-4-pregnenes of Formula I having ester groups such as at C-16 and at C-17, can be converted in known manner into 6-azido-4-pregnenes having free hydroxyl groups as, for example, by the action of acidic or alkaline saponification agents. When the 6-azido-4-pregnene of Formula I contains a chlorohydrin or bromohydrin at G-9 and C-11 (i.e. wherein X is halogeno and Y is (HJIOH), we prefer to hydrolyze in a slightly acid medium, e.g. utilizing 70% perchloric acid in methanolchloroform to minimize epoxide formation at C-9 and C-11. When hydrolyzing ester groups of compounds of Formula I not containing a 9(1l)-chlorohydrin or bromohydrin, We usually prefer to use methanolic sodium hydroxide keeping the reaction medium at about C. and under an inert atmosphere, e.g. Argon. If an ester group is present at C-11, it is convenient to convert the esterified compound to the free hydroxy analog by the action of the microorganism F lavobacterium dehydrogenans.

Procedures known in the art are utilized to convert a 17-hydroxy compound of our invention, e.g. of Formula I to the corresponding 17-acyl derivative, e.g. of Formula I. Thus, 17a-esters may be prepared by acylation of the corresponding 17a-hydroxy compounds. This is preferably effected by reaction of the steroid with an appropriate acid anhydride in the presence of a strong acid catalyst such as, e.g. p-toluenesulfonic acid, perchloric acid or strongly acidic cation exchange resins, or by using trifluoroacetic anhydride with an appropriate lower alkanoic acid. The reaction may be carried out in the absence of a solvent or in a non-polar solvent, e.g. carbon tetrachloride, benzene, toluene, methylene chloride and chloroform. Heating may or may not be necessary according to the reactivity of the reaction components.

The novel 20 keto-l6a,17a-dihydroxy compounds of Formula I may be converted to the 16a,17-alkylidenedioxy derivatives utilizing procedures known in the art, e.g. by reacting a 16a,17a-hydroxy steroid of Formula I (e.g. fi-azido-16a-hydroxy-6-dehydroprogesterone) with a ketone or aldehyde (e.g. acetone, acetylaldehyde) in the presence of a mineral acid (e.g. hydrochloric acid) whereby is obtained the corresponding 16u,17a-alkylidenedioxy derivative (e.g. 6-azidosl6a,17a-isopropylidenedioxy-4,6-

pregnadiene-3,20-dione.

The following examples are illustrative of the procedure employed in preparing the compounds of this inven- PHARMACEUTICAL FORMULATIONS OF 6-AZIDO'-.

16 METHYLENE. 17a ACETOXY-.4,6-PREGNA- DIENE-3,20-DIONB I Y (I) Tablet formulations Milligrams Formula A (5 mg.): 0 per tablet 6- azido 16- methylene-l7a-acetoxy-4,6-preg nadiene-3,20-dione Starch, food grade 5.0 Lactose, USP (spray dried) 89.5 Magnesium stearate, USP 0.5

. 100.0 Formula B (25 mg):

6-azido 16 methylene-17a acetoxy-4,6-pregv nadiene-3,20-dione 25.0 Starch, food grade v10.0 Lactose, USP (spray dried) l64.0 Magnesium stearate, USP 1.0

Pass the steroid through a high speed mill equipped with a to mesh screen. Blend the milled steroid with the starch in a suitable mixing vessel. Add an equal weight of the spray dried lactose to the blend and mix until uniform. Combine the resultant blend with the remainder of the spray dried lactose and mix, until uniform. Charge the magnesium'stearate with a portion of the active tablet mix and blend. Blend the magnesium stearate: mix with the remaiinng active tablet base. Continue mixing until uniform. Compress to targetweight (100.0 mg. for 5 mg. tablet and 200.0 mg. for 25 mg. tablet). 1

(II) Capsule formulation Milligrams Formula: 1 l per capsule 6-azido 16 methylene-17a-acetoxy-4,6 preg- Blend ingredients until uniformly mixed. Fill into hard gelatin capsule.

(HI) Parenteral suspension Milligrams per Formula A (5 mg.): r I p milliliter 6-azido 16 methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione- 5.00 Methyl cellulose 15 cps., USP 0.05. Sodium citrate, dihydrate 6.00 Benzyl alcohol, NF 9.00 Methylparaben, USP n 1.80 Propylparaben, USF 0.20 Water for injection (USP), qLs. ad; 1.00

FormulaB (25 mg):

6-azido 16 methylene-l7o -acetoxy-4,6-preg- 1 nadiene-3,20-dione 25.00 Methyl cellulose, 15 cps, USP L. 0.25 Sodium citrate, dihydrate .L 30.00 Benzyl alcohol, NF' 9.00 Methylparaben, USP 1.80" Propylparaben, USP 0.20 Water forinjection (USP), q.s.ad. 1.00

water (5 gm. for Formula .A or. 25 gm. for Formula B).;

Agitate until the methyl celluloseis thoroughly dispersed and wetted, Add approximately 30 l. of cold (0.5 KC.)

water for injection. Cool the entire mixture to 8 C. Dissolve the sodium citrate (600 gm. for Formula A or 3000 gm. for Formula B) in enough water for injection to make l. of solution. Slowly and with agitation add this solution to the cooled methyl cellulose solution. Dissolve the parabens (180 gm. of methyl and 20 gm. of propyl) in 900 gm. of benzyl alcohol which has been heated to 30 C. Charge this solution to the chilled methyl cellulose solution. Bring the resulting solution to 90 l. with water for injection and agitate until uniform. In a sterile area, pass the batch through a sterile filter. Aseptically transfer about 3.5 l. of the sterile methyl cellulose solution to a separate container reserving the remainder of the batch in a sterile stainless steel mixing tank. Slurry the steroid in a sterile colloid mill with about 2 l. of the separated methyl cellulose solution and add the slurry to the solution in the mixing tank. Rinse the slurry container and the mill with the remaining 1.5 l. of reserved methyl cellulose solution and add the rinse to the mixing tank. Adjust the volume in the mixing tank to 100 l. with water for injection and agitate until uniform. The batch aflords 100 l. of sterile suspension having the proportions of Formula A or Formula B.

Although the invention has been described above in terms of 6-azido-16-methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione as the essential active ingredient, other 6-azido-6-dehydroprogesterones of our invention as defined by Formula I hereinabove may be used in the above formulations and may be used'for the treatment of benign prostatic hypertrophy in a manner similar to that described for 6-azido-16-methylene-17u-acetoxy-6-dehydroprogesterone, the daily dosage of compound to be administered being dependent upon the severity of the patients condition.

EXAMPLE 1 6-azido 16 methylene 17 acetoxy-4,6-pregnadiene- 3,20 dione(6-azido-16-methylene-17a-acetoxy-6-dehydroprogesterone) (A) 6,3-azido-7a-hydroxy-16-methylene-17a-acetoxy- 4-pregnene-3,20-dione (1) Dissolve 4 g. of 6,7a-oxido-16-methylene-l7aacetoxy-4-pregnene-3,20-dione in 700 ml. of methanol and add a solution of 8 g. of sodium azide in 240 ml. of water and 4 ml. of acetic acid. Allow the reaction mixture to stand at room temperature overnight then pour into 2 liters of water and extract with chloroform. Dry the combined chloroform extracts over magnesium sulfate, evaporate the solvent to a residue and triturate the residue with ether and filter the resultant solid comprising 6,B-azido-7uhydroxy 16 methylene 17oz acetoxy-4-pregnene-3,20- dione. Purify by crystallization from ethyl acetate-ether to obtain 6p-azido-7a-hydroxy-16-methylene-17u-acetoxy- 4-pregnene-3,20-dione. [111 92.2 (dioxane);

methanol am.

In a similar manner treat each of 6a,7a-oxido-16-methylene-17a-propionoxy-4- pregnene-3,20-dione, 6u,7u-oxido-16-methylene-17a-n-butyroxy-4-pregnene- 3,20-dione, and 6a,7u-oxido-lo-methylene-l7a-valeroxy-4-pregnene- 3,20-dione with sodium azide in dilute acetic acid. Isolate and purify the resultant products in a manner similar to that described to obtain, respectively, 6B-azido-7a-hydroxy-16-methylene-17a-propionoxy- 4-pregnene-3,20-dione, GB-azido-h-hydroxy-16-methylene-l7a-n-butyroxy- 4-pregnene-3,20-dione, and 6B-azido-7u-hydroxy-1G-methylene-17a-valeroxy-4- pregnene-3,20-dione.

(2) Alternatively the compound of this example is prepared as follows. To a solution of 200 mg. of 6a,7aoxido-16-methylene-l7a-acetoxy-4-pregnene-3,20-dione in 40 m1. of methanol add 400 mg. of sodium azide and a solution of 40 mg. boric acid in 5 ml. of water. Stir the mixture of 50 C. for 35 minutes, add ml. of water then extract with chloroform. Wash the combined chloroform extracts with water, dry over magnesium sulfate, then concentrate in vacuo to a residue comprising 65- azido 7a hydroxy 16 methylene-17a-acetoxy-4-pregnene-3,20-dione which can be used without further purification in the esterification procedures 1B immediate following.

(B 6 fl-azido-7a-methanesulfonyloxyl 6-methylene- 17a-acetoxy-4-pregnene-3,20-dione (1) Add 1.5 ml. of methanesulfonyl chloride to a solution of 3 g. of 6fl-azido-7a-hydroxy-16-methylene-17macetoxy-4-pregnene-3,20-dione in 30 ml. of pyridine. Allow the reaction mixture to stand at room temperature for 17 hours then pour into water. Collect the resultant precipitate by filtration and dry in vacuo to obtain 65- azido 70c methanesulfonyloxy 16 methylene-lh-acetoxy-4-pregnene-3,20-dione. Purify by crystallization from ether; [a] =110.6 (dioxane).

In the above procedure, by utilizing p-toluenesulfonyl chloride in place of methanesulfonyl chloride, there is obtained the corresponding 7-p-tolenesulfonate ester, i.e. 6/8 azido 7a,17a dihydroxy-4-pregnene-3,20-di0ne 7-ptoluenesulfonate l7-acetate.

(2) Similarly, by carrying out the procedure described in paragraph 1 hereinabove, on each of the following:

6p-azido-7a-hydroxy-l d-methylene-17a-propionoxy-4- pregnene-3,20-dione, 6p-azido-7a-hydroxy-16-methylene-17a-n-butyroxy-4- pregnene-3,20-dione, and 6 3-azido-7a-hydroxy-16-methylene-17u-valeroxy-4- pregnene-3,20-dione, there is obtained respectively, 6,3-azido-h-methanesulfonyloxy-16-methylene-17apropionoxy-4-pregnene-3,20-dione, 6B-azido-7a-methanesulfonyloxy-16-methylene-17a-nbutyroxy-4-pregnene-3,20 dione, and 6B-azido-7u-methanesulfonyloxy-16-methylene-17avaleroxy-4-pregnene-3,20-dione.

(C) 6-azido-l6-methylene-l7a-acetoxy-4,6- pregnadiene-3,20-dione (1) Add 1.5 g. of 65-azido-Tu-methanesulfonyloxy-l6- methylene-l7a-acetoxy-4-pregnene-3,20-dione to a suspension of 0.750 g. of tetramethylammonium fluoride in ml. of acetonitrile. Allow the reaction mixture to stand at 60 C. for 35 minutes then remove the solvent in vacuo. Dissolve the resultant residue in chloroform and pour into water. Separate the solvent layers and wash the organic solvent layer with aqueous sodium bicarbonate, dry over magnesium sulfate, and evaporate the solvent to a residue comprising 6-azido-16-methylene-17uacetoxy-4,6-pregnadiene-3,20-dione. Purify by separation on preparative silica gel plates. Further purify by recrystallization from methanol to obtain 6-azido-l6-methylene-l7a-acetoxy-4,6-pregnadiene-3,20-dione; [M 63 (dioxane);

252 mu (e=14,616);

th 0! us."

298 lIl/L (e=14,616).

(2) Similarly, in the above procedure, by utilizing as starting compounds any one of the following:

6/3-azido-7a-p-toluenesulfonyloxy-1 6-methylene-17aacetoxy-4-pregnene-3,20-dione,

6p-azido-7a-methanesulfonyloxy-16-methylene-17apropionoxy-4-pregnene-3,20-dione,

fifl-azido-7u-methanesulfonyloxy-16-methylenee1flm-nv butyroxy;4epregnene-3,ZQ-dione, and, Y I I 6B-'azido-7a-methanesulfonyloxy 16-n1ethylene-17q- 1' v'aleroxy-4-pregnene-3,20dione,

th'ereis obtained, respectively,

6-azido-16-methylene17a acetoxy-4,6-pregnadiene-3,20'-,

dione,

6 azido-16-methylene-17at-propionoxy-4,6-pregnadiene- 3,20-dione,

6-azido-16-methylene-17a-n-butyroxy-4,6-pregnadiene- 3,20-dione, and

6-azido-16-meth'ylene-17a-valeroxy 4,6-pregnadiene- 3,20-dione.

(3) Alternatively, the compound of this example is prepared utilizing tetramethylammonium fluoride in dimethylformamide as follows. To a suspension of 100 mg. of tetramethylammonium fluoride in ml. dimethylformamide add 100 mg. 6B-azido-7a-methanesulfonyloxy- 16-methylene-17a-acetoxy-4-pregnene-3,20-dione. Allow the reaction mixture to stand at room temperature for 19 hours. Pour the reaction mixture into 175 ml. of water, add 5 g. sodium chloride, collect by filtration the resultant precipitate comprising 6-azido-16-methylene-17aacetoxy-4,6-pregnadiene-3,20-dione and dry said precipitate at 45 C. in vacuo. Extract the filtrate with methylene chloride and combine with 6-azido-16-methylene-17aacetoxy-4,6-pregnadiene-3,20-dione. Purify by preparative silica gel plate chromatography.

(4) Alternatively the compound of this example is prepared utilizing tetramethylammonium chloride as reagent as follows. To a suspension of 160 mg. of tetramethylammonium chloride in ml. of acetonitrile add 130 mg. 6p-azido-7a-methanesulfonyloxy-16-methylene- 17u-acetoxy-4-pregnene-3,20-dione. Allow the reaction mixture to stand at 60 C. for 26 hours then pour into 100 ml. of water and collect by filtration the resultant precipitate comprising 6-azido-16-methylene-17u-acetoxy- 4,6-pregnadiene-3,20-dione. Purify by drying the precipitate at 45 C. in vacuo and separating via preparative thick layer chromatography; yield=60 mg. (58% theoretical yield).

Alternatively, the compound of this example is prepared according to the following procedures D. and E.

(D) 6B-azido-7u,17a-diacetoxy-16-methylene-4- pregnene-3,20'-dione Add 14 ml. of acetic anhydride to a solution of 300 mg. of 6fi-azido-7a-hydroxy-16-methylene-17u-acetyl-4- pregnene-3,20-dione in 30 ml. of pyridine and allow the reaction mixture to stand at room temperature for 18 hours. Pour the reaction mixture into 400 m1. of water and stir for 20 minutes. Collect the insoluble fraction by filtration and dry in vacuo to yield a product comprising 651 azido-7u,17a-diacetoxy 16 methylene-4-pregnene-3,20- dione. Purify by crystallization from ethyl acetate: [01.] -119.3 (methanol).

In similar manner, by utilizing as starting compound in the above procedure any one of the following, i.e. 6fl-azido-7u-hydroxy-16-methylene-17a-propionoxy-4-. pregnene-3,2-0-dione, 6/3-azido-7a-hydroxy-16-methylene-17a-n-butyroxy-4- pregnene-3,20dione, and

6fi-azido-7a-hydroxy-16-methy1ene17u-valeroxy-4- pregnene-3,20-dione, respectively, the corresponding 7a-acetate ester:

respectively, the corresponding 7m-acetate ester:

6 fi-azido-7m-acetoxy- 1 6-methylene-17a-propionoxy-4- pregnene-3,20-dione,

6/3-azido-7m-acetoxy-1o-methylene-17u-n-butyroxy-4- pregnene-3,2;0-dione, and

6 3-azido-7a-acetoxy-16-methylene-17a-valeroxy-4- pregnene-3,20-dione.

(E) 6-azido 16=methylene 17u-acetoxy-4,6-pregnap 1 4 diene-3,20-dione v.

j i (1') In a manner similar to that described in Example 10 treat 6fi-azido-7a,17a diacetoxy 16 methylene-4- pregnene-3,'20-dione withtetramethylammonium fluoride in acetonitrile at 60? C. for 35- minutes; Isolate and purify the resultant product inia manner siinilar to that described to' obtain 6-azido-16 methylene l7-acetoxy-4,6-pregnadiene-3,20-dione. j

In similar manner treat ,with tetramethylammoni m fluoride in acetonitrile each of thet'ollowingz ,6/8-azido-7a-acetoxy-16methylene-l7a-propionoxy-4- pregnene-3,20-dione, 6fl-azido-7a-acetoxy-l6-methylene-17a-n-butyroxy-4- pregnene-3,20-dione, and 6fl-azido-7a-acetoxy-16-methylene-17a-valeroxy-4- pregnene-3,20-dione to obtain, respectively, 6-azido-16-methylene 17a-propionoxy-4,-pregnadiene- 3,20-dione, v6-azido-16-methylene-1 6 an-butyroxy-4,6-pregnadiene- 3,20-dione, and 6-azido-16-methylene-17u-valeroxy-4,6-pregnadiene- 3,20dione.

(2) Alternatively, the above procedure 1E1 may be carried out at room temperature for'18 hours (rather than 60 C. for 35 minutes) and there is formed 6-azido-16- methylene-l7a-acetoxy-4,6-pregnadiene-3,ZO-dione.

(3) Alternatively the compound of this example is prepared as follows. Dissolve 4 g. of tetramethylammonium fluoride pentahydratein 200 ml. acetonitrile and evaporate in vacuo to a residue. Repeat this procedure once again. To the resultant dry residue comprising tetramethylammonium fluoride add 2.3 g. of 6fi-aZidO 7ot,17ctdiacetoxy-4-pregnene-3,ZO-dione in ml. of acetonitrile. Stir the reaction mixture under an atmosphere of argon at 25 C. for two hours. Distill the solvent in vacuo to a residue comprising 6-azido-16 methylene-17a-acetoxy-4,6- pregnadiene-3,20-dione. Purify by chromatographing on Florisil (prewashedwith hexane),jeluting the product with acetone. Evaporate the combined eluants then crystallize the resultant residue with methanol to obtain 6- azido-16-rnethylene-l7a-acetoxy-4,6 pregnadiene 3,20 dione.

(4) Alternatively, the compound of this example is prepared utilizing tetramethylammonium fluoride pentahydrate, rather than the anhydrous reagent in the following manner. Add 2 g. of tetramethylammonium fluoride pentahydrate to 200 m1. of acetonitrile and heat the mixture with stirring until the tetramethylammonium fluoride pentahydrate liquifies. Cool to 25 C.'under an atmosphere of nitrogen then add 2.2 g. of 6/3-azido-7a,l7adiacetoxy-16-methyIene-4 pregnene-3,20-dioue and stir the reaction mixture under an atmosphere of nitrogen at 25 C. for 3 hours. Concentrate the reaction mixture to about 100 ml. in vacuo at 25 C. then pour into 1 liter of water and extract with ten 100 ml. portions of dichloromethane. Wash the combined extract with two 50 ml. portions of water, dry the dichloromethane over magnesium sulfate, then evaporate invacuo to a residue. Triturate the residue with about 25 ml. of boiling ether, cool to --20 C. and filter the solid fraction comprising 6-azido-16- methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione. Purify by crystallization from methanol.

EXAMPLE 2 Substituted 6-azido-l6-lower a1kylidene-17a-lower alkanoyloxy-4,6-pregnadiene-3,20-diones (A) 16-lower alkylidene-17u-lower alkanoyloxy-4,'6-

pregnadiene-3,20-diones temperature for 13 hours under an atmosphere of nitrogen. Evaporate the reaction mixture to a residue and extract the residue with ethyl acetate. Wash the combined organic extract with cold 7% aqueous sodium hydroxide, then with water, dry over magnesium sulfate, filter and evaporate to a residue comprising 16 ethylidene 17aacetoxy-4,6 pregnadiene-3,20-dione. Purify by crystallization from acetone/hexane.

(2) Alternatively, the compound of this example is prepared as follows. Add 10.2 g. of dichlorodicyanobenzoquinone to 10.0 g. of 16 ethylidene-17u-acetoxy-4-pregnene-3,20-dione in 600 ml. of dioxane, then bubble in anhydrous hydrogen chloride for minutes with stirring. Continue stirring at ambient temperature for 2.5 hours. Filter the reaction mixture and evaporate the filtrate in vacuo to a residue comprising 16-ethylidene-17a-acetoxy- 4,6-pregnadiene-3,20-dione. Purify by dissolving in ethyl acetate, washing the ethyl acetate solution with dilute sodium hydroxide then with water. Dry the organic solution over magnesium sulfate and evaporate in vacuo to a residue. Crystallize the residue in acetone hexane, to give 16-ethylidene-17a-acetoxy-4,6-pregnadiene-3,20-dione.

(3) In a manner similar to that described in Example 2A2 hereinabove, treat each of the following 4-pregnenes with dichlorodicyanobenzoquinone in dioxane:

Y 16-chloromethylene-17a-acetoxy-4- regnene-3,20-dione, 9a-fluoro-1lfl-hydroxy-16-chloromethylene-17a-acetoxy- 4-pregnene-3,20'dione, 9u-fluOrO-l 1/3-hydroxy-1-fiuoromethylene-17a-acetoxy- H 4-pregnene-3,20-dione, 16-fluoromethylene-l7ot-acetoxy-4-pregnene-3,20-dione,

and 1 1/3-hydroxy-16-chloromethylene-17a-acetoxy-4- pregnene-3,20-dione.

Isolate and purify the resultant respective products in a manner similar to that described in Example 2A2 hereinabove to obtain, respectively,

16-n-butylidene-17a-acetoxy-4,G-pregnadiene-3,20-dione, 911,1 lfl-dichloro- 1 6-methylene-17a-acetoxy-4,6-

pregnadiene-3,20-dione, 9a,1 Iii-dichloro-16 ethylidene-l7otacetoxy-4,6-

.pregnadiene-3,20-dione, 9ot-bromo-1 lfl-fluoro-lG-methylene-17a-acetoxy-4,6-

a pregnadiene-3,20-dione,'

' pregnadiene-3,20-dione,

I 9ot-fluoro16,-methylene-17u-acetoxy-4,6-pregnadiene- 3,11,20-trione, 1lfi-hydroxy-lG-methylene-17a-acetoxy-4,G-pregnadiene- 3,20-dione, 16-rnethylene-17a-acetoxy-4,6-pregnadiene-3,1 1,20-

trione, 16-methylene-17a-acetoxy-21-fluoro-4,6-pregnadiene- 3,20-dione, 9a,1 1fi-dichloro-21-fiuoro-16-methylene-17a-acetoxy- 4,6-pregnadiene-3,20-dione,

16-chloromethylene-17a-acetoxy-4,6-pregnadiene-3,20-

dione,

9a-fluoro-l 1,8-hydroxy-16-chloromethylene-17a-acetoxy- 4,6-pregnadiene-3,20-dione,

9a-fluoro-1 lfi-hydroxy-16-fiuoromethylene-17uacetoxy- 4,6-pregnadiene-3,20-dione,

1-fiuoromethylene-l7a-acetoxy-4,6-pregnadiene-3,20-

dione, and

1LB-hydroxy-16-chloromethylene-17a-acetoxy-4,6-

pregnadiene-3,20-dione.

(B) 60,70t-OXidO-16-10W6I alkylidene-lh-lower alkanoyloxy-4-pregnene-3,20-diones 1) To a solution of 210 g. of 16-ethylidene-17u-acetoxy-4,6-pregnadiene-3,20-dione in 75 ml. of acetone add 2 g. of m-chloroperbenzoic acid over a period of 2.5 hours. Heat the reaction mixture at reflux temperature for 5 hours, distill the solvent, dissolve the resultant residue in methylene chloride and pour the methylene chloride solution into water. Separate the aqueous layer from the organic solution, wash the organic solution with 200 ml. of 0.2 N sodium hydroxide, dry the organic solution over magnesium sulfate and remove the solvent in vacuo leaving a residue comprising 6a,7a-oxido-16-ethylidene-17macetoxy-4-pregnene-3,20-dione. Purify by dissolving in methylene chloride and separating via preparative thick layer chromatography to obtain 6a,7a-oxido-16-ethylidene-l7a-acetoxy-4-pregnene-3,20-dione which can be used without further purification in the following Example 2C.

(2) Alternatively, the compound of this example is prepared as follows. To 3.0 g. of l6-ethylidene-l7wacetoxy-4,6-pregnadiene-3,20-dione in 700 ml. of chloroform add 2.7 g. monoperphthalic acid and allow the reaction mixture to stand at room temperature for 60 hours. Isolate the resultant product by washing the chloroform reaction solution successively with aqueous sodium bicarbonate, water, ferrous sulfate solution and again with water. Dry the chloroform solution over magnesium sulfate and distill the solvent to a residue comprising 6a,7a-oxido-l6- ethylidene-l7a-acet0xy-4-pregnene-3,ZO-dione. Purify by crystallization from ethyl ether.

(3) Alternatively the compound of this example is prepared in a manner similar to that described in procedure 2B1 by treating 16-ethylidene-17a-acetoxy-4,6- pregnadiene-3,20-dione with m-chloroperbenzoic acid by using as solvent ml. of methylene chloride-tertiary butanol (1:1) (rather than acetone) and carrying out the reaction mixture at reflux temperature for 6 hours to obtain 6a,70t oxido-l6-ethylidene-17a-acetoxy-4-pregnene- 3,20-dione.

(4) In a manner similar to that described in Example 2B2 treat each of the 4,6-pregnadienes prepared as described in Example 1A3 With monoperphthalic acid in chloroform. Isolate and purify the resultant respective products in a manner similar to that described to obtain, respectively,

6a,7a-oxido-16-n-butylidene-l7a-acetoxy-4-pregnene- 3,20-dione,

6a,70t-OXid0-9ot,1 1 ,B-dichloro-16-methylene-17aacetoxy-4-pregnene-3,20-dione,

60:,7a-0XidO-9ot,1 l st-dichloro-16-ethylidene-17uacetoxy-4-pregnene3,20-dione,

6a,7u-oxido-9u-bromo-1lfi-fluoro-16-methylene-17aacetoxy-4-pregnene-3,20-dione,

6 05,7 oc-OXidO-9 a-fluoro-l lp-hydroxy-16-methylene-17uacetoxy-4-pregnene-3,20-dione,

611,7 a-oxido-9u-fluoro-16-methylene-17 u-acetoxy-4- pregnene-3,11,20-trione,

611,7 Ot-OXidO-l l 3-hydroxy-l6-methylene-17u-acetoxy-4- pregnene-3,20-dione,

6a,7a-oxido-1G-methylene-17a-acetoxy-4-pregnene- 3,1 1,20-trione,

6a,7u-oxido-16-methylene-17a-acetoxy-21-fluoro-4- pregnene-3,20-dione,

sat-276 6-azido-9a-fiuoro-16,B-methy1-17u-acetoxy-4,6-

pregnadiene-l1fl-ol-3,20-dione, 6-azidO-9a-fluor0- 16a-methy1-4,6 pregnadiene-1 15,170 diol-3,20-dione, 6-azido-9u-fluoro-1G ft-methyl-4,6-pregnadiene-1 1,8,17a-

diol-3,20-dione, I 6-azido-9wfluoro-16u-methyl-17a-acetoxy-4,6-

pregnadiene-3,1 1,20-trione, 6-azido-9u-fluoro-16B-methyl-17a-acetoxy 4,6-pregna diene-3, 11,20-trione, 6-azido-9a-fluoro-1 6a-methyl-4,6-pregnadiene-17a-o1- 3,1 1,20-trione, 6-azido-9a-fluoro-16fi-methyl-4,6 pregnadiene-17a-ol- 3,1 1,20-trione, 6-azido-16a-methyl-17a-acetoxy-21-fluoro-4,6-pregnadiene-3,20-dione, 6-azido-1613-methy1-17u-acetoxy-21-fluoro-4,6-pregnadiene-3,20-dione, 6-azido-1Ga-methyl-Z1-fluoro-4,6-pregnadiene-17a-ol- 3,20-dione, 6-azido-16 3-methyl-21-fluoro-4,6-pregnadiene-17a-ol- 3,20-dione, 6-azido-9a,2l-difluoro-4,6-pregnadiene- 17 oL-Ol-3,1 1,20-

trione, 6-azido-9a,21-difluoro-16u-methyl-4,6-pregnadiene-17a-ol- 3,1 1,20-trione, 6-azido9a,2 l-difiuoro-16fl-methyl-4,6-pregnadiene-17aol-3,1 1,20-trione, 6-azido-9a,21-difluoro-4,6-pregnadiene-1 1/5',17a-di01-3,Z0-

dione, 6-azido-9a,21-difluoro-16a-methy1-4,6-pregnadiene-1 15,

17a-diol-3,20-dione, 6-azido-9a,21-difluoro-16B-methyl-4,6-pregnadiene- 1 1 fl-17oc-'diol-3,20-dionc, 6-azido-21-fluoro-4,6-pregnadiene-17a-ol-3,11,20

trione, 6-azido-16a-methyl-21-fiuoro-4,6-pregnadiene-17u-ol- 3,11,20-trione, 6-azido-1 fifl-methyl-Z l-fluoro-4,6-pregnadiene-1 7a-01- 3,11,20-trione, 6-azido-21-fiuoro-4,6-pregnadiene-17a-ol-3,20-dione, 6-azido-16a-methyl-2.1-fluoro-4,6-pregnadiene-17a-ol- 3,20-dione, fi-azido-l 6;.8-methy1-21-fluoro-4,6-pregnadiene- 17aol-3,20-dione, 6-azido-4,6-pregnadiene-3 ,ZO-dione, 6-azido- 1 6a-methy1-4, 6-pregnadiene-3,20-dione, 6-azido-16f3-methyl-4,6-pregnadiene-3,20-dione, 6-azido-21-fiuoro-4,6-pregnadiene-3,20-dione, 6-azido-16a-methyl-21-fluoro-4,6-pregnadiene-3,20-

dione, 6-azido-16fi-methyl-21-fluoro-4,6-pregnadicne-3,20-

dione, 6-azido-4,6-pregnadiene-3 1 1,20-trione, 6-azido-1 6a-methyl-4,6-pregnadiene-3,1 1,20-trione, 6-azido-16,3-methy1-4,6-pregnadiene-3,1 1,20-trione, 6-azido-4,6-pregnadiene-1 1fl-ol-3,20-dione, 6-azido-16a-methyl-4,-pregnadiene-1 1fi-ol-3,20-dione, 6-azido-16fi-methylr4,6-pregnadiene-11fl-ol-3,20-dione,' 6-azido-9a,1 1fi-dichloro-4,fi-pregnadiene-3,20-dione, 6-azido-9a, 1 lp-dichloro-16u-methyl-4,6-pregnadiene 3,20-dione, 6-azido-9u,1lfl-dichloro-16fl-methyl-4,6-pregnadiene- 3 ,20-dione, 6-azido-9u-bromo-1 15-chloro-4,6-pregnadiene- 3,20-dione, I 6-azido-9a-bromo- 1 1 B-chloro- 16a-methy1-4,6 pregnadiene-3,20-dione, 6-azido-9 a-bromo- 1 1/3-chloro-16 8-methy1-4,6-

pregnadiene-3,20-dione, 6-azido-9a, l IB-dichloro-Z1-fluoro-4,6-pregnadiene- 3,20-dione, 6-azido-9a,1l 8-dichloro-2l-fluoro-l6amethyl-4,6-

pregnadiene-3,20-dione,

6-azido-9a,1 lfi-dichloro-Z1-fluoro-16B-methyl-4,6-

pregnadiene-3,20-dione.

EXAMPLE 4 Alternate procedure for preparation of 6-azido 16- methylene 17a hydroxy 4,6 pregnadiene-3,20- dione and the 17a-acetate thereof (A) 6B-azido-7a-hydroxy-16,8-methyl-16a,17a-oxido- 4-pregnene-3 ,20-dione To a solution of 8 gpof 6a,7oz;16oz,17a-biS-OXidO-l6fimethyl 4 pregnene 3,20 dione in 1500 ml. of methanol add a solution of 20 g. sodium azide in 100 ml. of water. Allow the reaction mixture to stand at room temperature overnight then pour into water, extract with chloroform and dry the combined extracts over magnesium sulfate. Filter the chloroform solution and evaporate to a residue comprising 6fi-azido 7a hydroxy 46B methyl- 16a,17a oxido 4 pregnene 3,20 dione. Purify by crystallization from ethyl acetate, M.P. 217 C. (dec.) [(11 +535 (dioxane).

(B) 6fl-azido-7a,17a-diaeetoxy-16-methy1ene-4- pregnene-3 ,20-dione To a solution comprising 520 mg. of 6fl-E1ZidO-7oc-hydroxy-16 3-methyl-16a,17a oxido 4 pregnene-3,20- dione in 8 ml. of acetic acid and mg. of p-toluenesulfonic acid cooled to 5 C. add 4 ml. of trifiuoroacetic anhydride. Allow the reaction mixture to stand at room temperature for 25 minutes then pour into water and collect by filtration the resultant precipitate comprising 6,6-azido 711,170; diacetoxy-16-methylene-4-pregnene- 3,20-dione. Purify by drying the precipitate and crystallizing from ethyl acetate-ether to obtain 280 mg. of 6B- aZid0-7oz,17oz diacetoxy 16 methylene-4-pregnene- 3,2'0-dione: [11] 1l9.3 (dioxane).

(C) 6-azido-16-methylene-17a-acetoxy-4,6-pregnadiene- 3,20-dione In a manner similar to that described in Example 1E1 treat 6p-azido 7u,17m diacetoxy-l6-methylene-4-pregnene-3,20-dione with tetramethylammonium fluoride in acetonitrile at 60 C. for 35 minutes. Isolate and purify the resultant product in the manner described to obtain 6-azido-16-methylene-17a-acetoxy 4,6-pregnadiene-3,20- dione.

The corresponding 6 azido-17a-hydroxy-4,6-pregnadiene is obtained via the 16fimethyl-16u,17a-oxido intermediate according to following procedures D, E, and F.

(D) 618-azido-7a-methanesulfonyloxy-16fl-methyl- 16a,17u-oxido-4-pregnene-3,20-dione Add 0.75 ml. of methanesulfonyl chloride to a solution of 1.5 g. of 6p-azido-7a-hydroxy-16fl-methyl-16a,17aoxido-4-pregnene-3,20-dione in 15 ml. of pyridine. Allow the reaction mixture to stand at room temperature for 17 hours then pour into water and extract with methylene chloride, wash the combined methylene chloride extracts with dilute aqueous sodium bicarbonate solution then with water and dry over magnesium sulfate. Filter the methylene chloride solution and evaporate to a residue comprising 1.65 g. of 6fl-azido-7a-methanesulfonyloxy- 16fl-methyl-16a,17a-oxido-4-pregnene-3,20-dione.

In the above procedure by utilizing p-toluenesulfonyl chloride instead of methanesulfonyl chloride, there is obtained the corresponding p-toluenesulfonate ester, Le. 65- azido-7a p toluenesulfonyloxy-l6p-methyl-16a,17aoxido-4-pregnene-3,20-dione.

(E) '6 3-azido-7a-methanesu1fonyloxy-1-methylene- 17a-hydroxy-4-pregnene-3,20-dione To a solution of 0.8 g. of Gfl-azido-7a-methanesulfonyloxY-lGfi-methyl-l6a,17a-oxido 4 pregnene-3,20-dione in 17 ml. of acetic acid, at room temperature add 1.7 ml. of a 10% solution of hydrobromic acid in acetic acid.

Allow the reaction mixture to stand at room temperature for 30 minutes then dilute with 2 liters of water. Extract with methylene chloride and wash the methylene chloride extracts with water and evaporate to a residue comprising 613 azido 70c methanesulfonyloxy-16-methylene-17othydroxy-4-pregnene-3,20-dione which is used without further purification in following procedure F.

In similar manner, by treating 6/3-azido-7u-p-toluenesulfonyloxy-l6/3-methyl-16a,17a oxido 4 pregnene- 3,20-dione with hydrobromic acid in acetic acid there is obtained 6,8-azido 70c p-toluenesulfonyloxy-16-methylene-17ot-hydroxy-4-pregnene-3,20-dione.

(F) 6-azido-16-methylene-17a-hydroxy-4,6-pregnadiene- 3,20-dione In a manner similar to that described in Example 1C1 treat 6fl-azido 7oz methanesulfonyloxy-l6-methylene- 17a-hydroxy-4-pregnene-3,20-dione prepared as described in preceding Example 4E with tetramethylammonium fluoride in acetonitrile. Isolate and purify the resultant product in a manner similar to that described to obtain 6-azido-16-methylene-17a-hydroxy 4,6 pregnadiene- 3,20-dione.

In similar manner treat 6,8-azido-7a-p-toluenesulfonyloxy 16 methylene-17a-hydroxy-4-pregnene-3,20-dione with tetramethyl-ammonium fluoride in acetonitrile to obtain 6-azido 16 methylene-17a-hydroxy-4,6-pregnadiene-3,20-dione.

Alternatively, the 6-azido-16-methylene-17a-hydroxy- 4,6-pregnadiene of this example is prepared from the compound of Example 4D according to following procedures 46 and 4H.

(G) 6-azido-16fl-methyl-l6u,17a-oxido-4,6-pregnadiene- 3,20-dione In a manner similar to that described in Example 1E1 except that the reaction mixture is allowed to stand at 60 C. for 16 hours rather than 30 minutes, treat 6 6- azido 7a-methanesulfonyloxy-16fl-methyl-16a,17a-oxido- 4-pregnene-3,20-dione with tetramethylamrnonium fluoride in acetonitrile. Isolate the resultant product via preparative thin layer chromatographic techniques to ob tain -6-azido16,8-methyl-16u,17a-oxido-4,6-pregnadiene-3, 20-dione.

(*H) 6-azido-16-methylene-17u-hydroxy-4,6-pregnadiene- 3,20-dione In a manner similar to that described in Example 4E treat 6-azido-165-methyl-16a,17a-oxido-4,6-pregnadiene- 3,20-dione with hydrobromic acid in acetic acid at room temperature for 30 minutes. Isolate and purify the resultant product in a manner similar to that described to obtain 6 azido 16 methylene-17ot-hydroxy-4,6-pregnadiene-3,20-dione.

The 17a-acetoxy compound of this example is also prepared by treating 6-azido-16p-methyl- 16:1,17 a-oxido-4,6- pregnadiene-3,20-dione with acetic acid, p-toluenesulfonic acid and trifluoroacetic anhydride in the manner described in Example 4B to obtain 6-azido-16-methylene-17ocacetoxy-4,6-pregnadiene-3,20-dione.

EXAMPLE Alternate method for preparing 6-azido-16-methylene- 17a-acetoxy-4,6-pregnadiene-3,20-dione Stir a mixture of 100 mg. of 6fl-azido-7a,17x-dihydroxy- 16-methylene-4-pregnene-3,20-dione 17-acetate in 3.15 ml. of dioxane, 3.15 ml. of acetic acid and 0.7 ml. concentrated hydrochloric acid at 25 C. for 24 hours. Then add 60 ml. of methylene chloride and wash the methylene chloride solution with water then dilute aqueous sodium bicarbonate solution and again with water. Dry the methylene chloride solution over magnesium sulfate, filter and evaporate the solution in vacuo to a residue 38 comprising 6-azido-16-methylene-l7u-acetoxy-4,6-pregnadiene-3,20-dione. Purify by chromatography on a preparative silica gel plate.

In similar manner, treat 6fi-azido-7a,l7ot-diacetoxy-l6- methylene-4-pregnene-3,ZO-dione with concentrated hydrochloric acid in dioxane and acetic acid to obtain 6- azido 16 methylene-17a-acetoxy-4,6-pregnadiene-3,20- dione.

Similarly, by treating the 6/8-azido-7a-hydroxy-4- pregnenes and the 7a-lower alkanoates thereof prepared as described in preceding Examples 1-4 with concentrated hydrochloric acid there is obtained the corresponding 6-azido-4,6-pregnadiene.

EXAMPLE 6 '6-azido-16-methylene-17a-acetoxy-1,4,6-pregnatriene- 3 ,20-dione Prepare a hydrochloric acid-dioxane solution by adding 0.5 ml. of concentrated hydrochloric acid and 5 ml. of water to 49.5 ml. of dioxane. To 7.8 ml. of this hydrochloric acid-dioxane solution add 132 mg. of 6-azido-l6- methylene 17a acetoxy-4,6-pregnadiene-3,20-dione and 146 mg. of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ). Under an atmosphere of nitrogen warm the solution to 60 C. with stirring for 30 minutes. Pour the reac tion mixture into ml. of water and extract with ethyl acetate. Wash the combined ethyl acetate extracts with concentrated aqueous sodium sulfite solution and then with water. Dry the ethyl acetate solution over magnesium sulfate and filter. Pass the solution through a Florisil column and evaporate the eluant in vacuo to a residue comprising 6 azido 16 methylene a acetoxy-1,4,6- pregnatriene-3,20-dione. Purify by fractional crystallization from di-isopropyl ether-hexane.

In similar manner by treating each of the 6-azido-4,6- pregnadiene-3,20-diones prepared in preceding Examples 1-5 with DDQ there is obtained the corresponding 6- azido-1,4,6-pregnatriene-3,20-dione.

EXAMPLE 7 Preparation of 21-iodo and 21-bromo-6-azido-4,6-pregnadienes and use thereof as intermediates (A) 6-azido-4,6-pregnadiene-17u,21-diol-3,20-dione 2 l-methanesulfonates (1) The requisite 6-azido-21-hydroxy-4,6-pregnadiene intermediates are prepared by treating the corresponding 60,7u-OXidO-4-PI6gI1CI16- 17a,21-diol-3,20-dione 21-lower alkanoate in dioxane and methanol with sodium azide in aqueous acetic acid followed by treatment of the resultant 6,3 azido 7a-hydr0Xy-4-pregnene-17a,2l-diol-3,20-dione 21-lower alkanoate with acetic anhydride in pyridine to obtain the corresponding 7-acetate ester, i.e., 6B-azido-7aaeetoxy 4 pregnene-17a,21-diol-3,20-dione 21-lower -a1- kanoate. Treatment of the foregoing with tetrarnethylammonium fluoride in acetonitrile yields 6-azido-4,6- pregnadiene-17a,21-diol-3,20-dione 21-lower alkanoate which upon hydrolysis in aqueous methanol with sodium hydroxide at 0 C. yields the necessary 6-azido4,6-pregnadiene-17a,21-diol-3,20-dione intermediate.

To a solution of 5 g. of 6-azido-4,6-pregnadiene-1704,21- diol-3,11,20-trione in 50 ml. of pyridine cooled to --20 C., add dropwise 5 ml. of methanesulfonyl chloride. Stir at -20 C. for 30 minutes then pour into water and stir for 2 hours longer at room temperature. Filter and dry the resultant precipitate comprising 6-azido-4,6-pregnadiene 1711,21 diol 3,11,20-trione ZI-methanesulfonate. Purify by crystallization from acetone-hexane.

(2) In a similar manner treat each of the following with methanesulfonyl chloride in pyridine at 20 C 6-azido-4,6-pregnadiene-1 1 8,17a,21-triol-3,20-dione, 6-az1do-9a-fiuoro-16u-methyl-4, 6-pregnadiene-1 15,170,

21-triol-3,20-dione,

39 6-azido-9u-fiuoro-1Gfl-methyl-4,6-pregnadiene-1 15,171,

21-triol-3,20-dione, 6-azido-1-6ot-methyl-4,6-pregnadiene-17a,2 1-diol-3,1 1,20-

trione, 6-azido-16B-methyl-4,6-pregnadiene-17a,21-dio1-3 ,1 1,20-

trione, 6-azido-9a-fluoro-16a, 17ot-iso-propylidenedioXy-4,6-

pregnadiene-l 1,8,21-diol-3,20-dione, 6-azido-9a-fluoro- 16-methylene-4,6-pregnadiene-1 1 6,170,

21-triol-3,20-dione, and 6-azido-4,6-pregnadiene-21-ol-3,20-dione.

Isolate and purify the resultant respective products in a manner similar to that described in Example 7A1 to obtain, respectively:

6-azido-4,6-pregnadiene-11p,l7a,21-triol-3,20-dione ZI-methanesulfonate, 6-azido-9'a-fluoro-l 6a-methyl-4,6-pregnadiene-1 113,17a,

2-1 -trio1-3,20-dione 21-methanesulfonate, 6-azido-9wfluorol6B-methyl-4,6-pregnadiene-l lfl,17u,

21 -triol-3,20-dione 21-methanesulfonate, 6-azido-16ot-methy1-4,6-pregnadiene-170:,21-di01-3,11,20-

trione 2 l-methanesulfonate, 6-azido-16/3-methy1-4,6-pregnadiene-17a,21-di0l-3,11,20-

trione 21-methanesulfonate, 6-aZldO-9a fllIOlO-160L,17OL-lSO-PIOPYlidBIlCdiOXY-i,6-p18gnadiene-l 1B,21-diol-3,20-dione 2 l -methanesulfonate, 6-azido-9a-fluoro-16-methylene-4,6-pregnadiene-11[3,l7ot,

21 -triol-3,20-dione 21 -methanesulfonate, and 6-azido-4,6-pregnadiene-2-ol-3,ZO-dione 2 l-methanesulfonate.

(B) 6-azido-2 1-iodo-4-pregnene- 17 a-ol-3,20-diones (1) To 3.5 g. of 6-azido-4,6-pregnadiene-17ot,2l-diol- 3,11,20-trione 2l-methanesulfonate in 52.5 ml. of acetone add 3.5 g. of sodium iodide. Heat the reaction mixture at reflux temperature for 20 minutes then pour into 500 ml. of water, filter and air dry the resultant precipitate comprising 6 azido-21-iodo-4,6-pregnadiene-l7u-ol-3,11, 20-trione. Purify by crystallization from acetone-hexane.

(2) In a similar manner treat each of the methanesulfonate ester derivatives. prepared as described in Example 7A2 with sodium iodide in acetone in the manner described in Example 7B1 to obtain, respectively:

6-azido-21-iodo-4,6-pregnadiene-115,17a-di0l-3 ,20-dione,

6-azido-9u-fiuoro-2l-iodo-l6ot-methyl-4,6-pregnadiene- 11B,17a-diol-3,20-dione,

6-azido-9a-fluoro-2l-iodo-16,B-methyl-4,6-pregnadiene- 11,9, l7a-di0l-3 ,20-dione, 6-azido-l6a-methyl-2l-iodo-4,6-pregnadiene-17u-o1-3,

11,20-trione, 6-azido-16,6-methyl-21-iodo-4,6-pregnadiene-17a-ol-3,

11,20-trione, 6-azido-9a-fiuoro-2l-iodo-l6a,l7a-iso-propylidenedioxy- 4,6-pregnadiene1 lfl-ol-3,20-dione, 6-azido-9a-fluoro-2 l-io do- 1 6-methylene4,6-pregnadiene- 11fi,17ot-diOl-3,20-di01'16, and 6-azido-21-iodo-4,6-pregnadiene-3,20-dione.

(3) By following the procedure described in Example 7B1 by utilizing sodium bromide instead of sodium iodide there is obtained the corresponding 21-bromo compound, i.e. 6-azido-2lbromo-4,6-pregnadiene-17a-ol-3,11,20- trione. Similarly, the 21-bromo analogs of the 21-iodo compounds listed in Example 7B2 are prepared by treating the corresponding 21-methanesulfonates in acetone with sodium bromide.

(C) 6-azido-4-pregnene-17a,21-di0l-3,20-dione 2l-phosphate esters (1) To 43 ml. of methanol at room temperature add dropwise with stirring 24 ml. of 85% aqueous phosphoric acid. Add cautiously 75.4 ml. of triethylamine followed by 12.7 g. of 6-azido-21-iodo-4,6-pregnadiene-17aol-3,l-1,20-trione. Warm the reaction mixture on a steam 40 bath for 30 minutes then with stirring pour the reaction mixture into water (260 ml.) containing concentrated hydrochloric acid (72.5 ml.). Filter the resultant precipitate comprising 6-azido-4,6-pregnadiene-17a,21-diol-3,11,20- trione 21-phosphate. Purify by crystallization from aqueous acetone.

(2) In a similar manner treat each of the 2l-iodo- 4-pregnenes prepared as described in Example 7B2 with phosphoric acid in triethylamine and methanol. Isolate and purify the resultant respective products in a manner similar to that described to obtain respectively:

6-azido-4,6-pregnadiene-l 1 p, 17 a,2 1-triol-3,20-dione 21- phosphate, 6-azido9a-fluoro16a-methyl-4,6-pregnadiene-1 15,170,

21-triol-3 ,20-dione 2 l-phosphate, 6-azido-9u-fluoro-165-methyl-4,6pregnadiene-l 15,17,

2l-triol-3,20-dione 2l-phosphate, 6-azido-16a-methyl-4,G-pregnadiene-17a,21-diol-3,1 1,

20-trione 21-phosphate, 6-azido-16/3-methyl-4,6-pregnadiene-17a,21-dio1-3,l 1,20-

trione 21-phosphate, 6-azido-9wfluoro-l6a,17a-iso-propylidenedioxy-4,6-

pregnadiene-l 1,8,2 l-diol-3 ,20-dione 21-phosphate, 6-azido-9a-fluoro-16-methylene-4,6-pregnadiene-1 15,17a,

21-triol-3,20-dione Zl-phosphate, and 6-azido-4, 6-pregnadiene-2 l-ol-3 ,20-dione 2 l-phosphate.

(D)Preparation of 6-azido-6-dehydroprogesterones from the corresponding 6-azido-21-iodo-6-dehydroprogesterone 1) To 0.9 g. of 6-azido-21-iodo-4,6-pregnadiene-17aol-3,11,20-trione in 20 ml. of dimethylformamide add 2.2 g. of sodium iodide followed by 5 ml. acetic acid, and stir at 45 C. for 30 minutes. Pour into dilute aqueous sodium bisulfite and collect the resultant precipitate comprising 6-azido-4,6-pregnadiene-17a-ol-3,l1,20-t1'ione.

In similar manner 6-azido-21-bromo-4,6-pregnadiene- 17B-ol-3,20-dione upon treatment with sodium iodide in dimethylformarnide and acetic acid is reduced to the corresponding progesterone, i.e. 6-azido-4,6-pregnadiene-17aol-3,1 1,20-trione.

(2) In similar manner treat each of the 21-iodo derivatives prepared as described in Example 7B2 with sodium iodide in dimethylfor mamide and acetic acid to obtain respectively:

6-azido-4,6-pregnadiene-1 118, 17a-diol-3 ,20-dione, 6-azido-9wflu0ro-16ot-methyl-4,6-pregnadiene-1 lfi, 17adiol-3,20-dione, 6-azido-9ot-fiuoro-16 8-methyl-4, 6-pregnadiene-l 15,170:-

diol-3,20-dione, 6-azido-16a-methyl-4,6-pregnadiene-1711-01-3 ,1 1,20-trione, 6-azido- 16B-methyl-4,6-pregnadiene-l7u-ol-3,1 1,20-trione, 6-azido-9a-fluoro-16a,17u-iso-propylidenedioxy-4,6-

pregnadiene-l1;8-0l-3,20-dione, 6-azido-9a-fluoro-16-methylene-4,6-pregnadiene-1 1p,

17ozdi0l-3,20-Cli0l1e, and 6-azido-4,6-pregnadiene-3,20-dione.

EXAMPLE 8 Hydrolysis of 6-azido-17a-acyloxy-4,6-pregnadiene-3,20- diones to the corresponding 17-hydroxy derivatives To a solution of 2 g. of 6-azido-16-methylene-17uacetoxy-4,6-pregnadiene-3,20-dione in 15 ml. of tetrahydrofuran, 10 ml. of methanol and 5 ml. of water at 0 C. add 5 ml. of 1 N aqueous sodium hydroxide with stirring while bubbling nitrogen through the solution. Allow the solution temperature to rise to room temperature and continue stirring under a blanket of nitrogen at room temperature for another two hours, then neutralize the reaction mixture with acetic acid, pour into water and filter the resultant precipitate comprising 6-azido-16-methylene- 17ot-hydroxy-4,6-pregnadiene-3,20 dione. Purify by crystallization from acetone-hexane.

In a similar manner the 17a-acyloxy derivatives of the 6-azido-4,6-pregnadienes and 6-azido-1,4,6-pregnatrienes 

